System and methods for processing analyte sensor data for sensor calibration

ABSTRACT

Systems and methods for processing sensor analyte data are disclosed, including initiating calibration, updating calibration, evaluating clinical acceptability of reference and sensor analyte data, and evaluating the quality of sensor calibration. The sensor can be calibrated using a calibration set of one or more matched sensor and reference analyte data pairs. Reference data resulting from benchtop testing an analyte sensor prior to its insertion can be used to provide initial calibration of the sensor data. Reference data from a short term continuous analyte sensor implanted in a user can be used to initially calibrate or update sensor data from a long term continuous analyte sensor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/373,628, filed on Mar. 9, 2006, which claims the benefit of U.S.Provisional Application No. 60/660,743 filed on Mar. 10, 2005, each ofwhich is incorporated herein by reference in its entirety, and each ofwhich is hereby made a part of this specification.

FIELD OF THE INVENTION

The present invention relates generally to systems and methods foranalyte sensor data processing. Particularly, the present inventionrelates calibration of sensors.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which can cause anarray of physiological derangements (e.g., kidney failure, skin ulcers,or bleeding into the vitreous of the eye) associated with thedeterioration of small blood vessels. A hypoglycemic reaction (low bloodsugar) can be induced by an inadvertent overdose of insulin, or after anormal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a diabetic person carries a self-monitoring bloodglucose (SMBG) monitor, which typically comprises uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a diabeticwill normally only measure his or her glucose level two to four timesper day. Unfortunately, these time intervals are so far spread apartthat the diabetic will likely find out too late, sometimes incurringdangerous side effects, of a hyper- or hypo-glycemic condition.Alternatively, a long term sensor implanted in a diabetic person canprovide substantially continuous blood glucose measurements to areceiver carried by the diabetic and obviate the finger pricking method.Due to its biological interface, after it is implanted a long termsensor typically requires a waiting period after which its sensor datamust be calibrated using the finger prick method or the like.

SUMMARY OF THE INVENTION

Systems and methods for providing blood glucose measurements are neededthat can shorten the calibration process of a long term sensor, avoid orreduce dependence on using the finger prick method during calibration,or overcome other problems known in the art. Systems and methods aredisclosed that provide calibration of a long term sensor data usingsensor data from another sensor. In one embodiment, the inventionincludes a method for calibrating an analyte sensor, the methodincluding receiving sensor data from a first analyte sensor, receivingsensor data from a second analyte sensor, and calibrating the sensordata from the first analyte sensor using the sensor data from the secondanalyte sensor.

In one aspect of the first embodiment, the first analyte sensor is along term substantially continuous analyte sensor and the second analytesensor is a short term substantially continuous sensor. One embodimentof this aspect further includes receiving sensor data from a set ofsubstantially continuous analyte sensors, the set of sensors comprisingone or more short term sensors, and the set of sensors being employed ina host in series such that the overall time period during which sensordata from the set of sensors is received is greater than the usefullifespan of one of the short term sensors and calibrating the sensordata from the first analyte sensor using the sensor data from the secondanalyte sensor and the set of sensors. In another embodiment of thisaspect calibrating the long term sensor data further includes usingsensor data from the short term analyte sensor to update the calibrationof the long term analyte sensor.

In a second aspect of the first embodiment, the first and second analytesensors are glucose sensors.

In a third aspect of the first embodiment, the sensor data from thefirst analyte sensor includes at least one sensor data point, whereinthe sensor data from the second analyte sensor includes at least onedata point, and wherein calibrating the sensor data further comprisesforming one or more matched data pairs by matching at least one sensordata point from the first analyte sensor to at least one sensor datapoint from the second analyte sensor and forming a calibration setcomprising at least one matched data pair.

In a fourth aspect of the first embodiment, the sensor data from thefirst analyte sensor includes at least six sensor data points, whereinthe sensor data from the second analyte sensor includes at least sixsensor data points, and wherein calibrating the sensor data furthercomprises forming at least six matched data pairs by matching eachsensor data point from the first analyte sensor to a correspondingsensor data point from the second analyte sensor and forming acalibration set comprising at least six matched data pairs.

In a fifth aspect of the first embodiment, the sensor data from thefirst analyte sensor includes at least twenty sensor data points,wherein the sensor data from the second analyte sensor includes at leasttwenty sensor data points, and wherein calibrating the sensor datafurther comprises forming at least twenty matched data pairs by matchingeach sensor data point from the first analyte sensor to a correspondingsensor data point from the second analyte sensor and forming acalibration set comprising at least twenty matched data pairs.

In a sixth aspect of the first embodiment, the method further includesconstructing a first curve from the sensor data from the first analytesensor and constructing a second curve from the sensor data from thesecond analyte sensor,wherein calibrating the sensor data from the firstanalyte sensor comprises matching the first curve with the second curve.

In a seventh aspect of the first embodiment, the first analyte sensor isa short term substantially continuous analyte sensor and the secondanalyte sensor is a short term substantially continuous analyte sensor.

In a eighth aspect of the first embodiment, the first analyte sensor isa long term substantially continuous analyte sensor and the secondanalyte sensor is a long term substantially continuous analyte sensor.

In a ninth aspect of the first embodiment, the first analyte sensor is ashort term substantially continuous analyte sensor and the secondanalyte sensor is a long term substantially continuous analyte sensor.

In a tenth aspect of the first embodiment, the method further includesreceiving data from a non-continuous reference source, and wherein saidcalibrating further includes using data from the non-continuousreference source to calibrate the sensor data from the second analytesensor.

In an eleventh aspect of the first embodiment, the non-continuousreference source is a blood glucose monitor.

In a twelfth aspect of the first embodiment, the non-continuousreference source is an in-vitro calibration.

In a thirteenth aspect of the first embodiment, the non-continuousreference source is an optical sensor.

In a fourteenth aspect of the first embodiment, calibrating the longterm sensor data further includes using sensor data from the short termanalyte sensor to update the calibration of the long term analytesensor.

In a second embodiment, the invention includes a method of processingdata from a substantially continuous analyte sensor, the methodincluding testing an analyte sensor prior to insertion into a host todetermine at least one sensor data characteristic, employing the analytesensor in the host, receiving sensor data from the analyte sensor, andcalibrating the sensor data using the sensor data characteristic.

In one aspect of the second embodiment, the substantially continuousanalyte sensor is a short term sensor.

In a second aspect of the second embodiment, the substantiallycontinuous analyte sensor is an implantable long term sensor.

In a third aspect of the second embodiment, the method further includesreceiving reference data from a reference analyte monitor, the referencedata comprising at least one reference data characteristic andcalibrating the sensor data using the reference data characteristic.

In a fourth embodiment, the invention includes a system for calibratinga substantially continuous analyte sensor, the system including a firstsubstantially continuous analyte sensor, a second substantiallycontinuous analyte sensor, a first sensor data receiving module operablylinked to said first sensor and configured to receive at least onesensor data point from said first sensor, a second sensor data receivingmodule operably linked to said second sensor and configured to receiveat least one sensor data point from said second sensor, and a processormodule in data communication with the first sensor data receiving modulelinked to said first sensor and further in data communication with thesecond sensor data receiving module linked to said second sensor, saidprocessor module configured to calibrate the sensor data from the firstsensor using sensor data from the second sensor.

In one aspect of the fourth embodiment, the processor module is furtherconfigured to match at least one time-matched data point from said firstanalyte sensor and said second analyte sensor to form at least onecalibration set for calibrating the first analyte sensor including atleast one matched data pair.

In a second aspect of the fourth embodiment, the first analyte sensor isa long term substantially continuous analyte sensor and the secondanalyte sensor is a short term substantially continuous analyte sensor.

In a third aspect of the fourth embodiment, the first analyte sensor isa short term substantially continuous analyte sensor and the secondanalyte sensor is a short term substantially continuous analyte sensor.

In a fourth aspect of the fourth embodiment, the first analyte sensor isa long term substantially continuous analyte sensor and the secondanalyte sensor is a long term substantially continuous analyte sensor.

In a fifth aspect of the fourth embodiment, the first analyte sensor isa short term substantially continuous analyte sensor and the secondanalyte sensor is a long term substantially continuous analyte sensor.

In a sixth aspect of the fourth embodiment, the first substantiallycontinuous analyte sensor and said second substantially continuousanalyte sensor are each glucose sensors.

In a fifth embodiment, the invention includes a method forsimultaneously utilizing at least two analyte sensors, the methodincluding receiving sensor data from a first analyte sensor, receivingsensor data from a second analyte sensor, and processing the sensor datafrom the first analyte sensor using the sensor data from the secondanalyte sensor.

In one aspect of the fifth embodiment, the sensor data from the secondanalyte sensor comprises time delay information and processing comprisesmodifying the sensor data from a first analyte sensor responsive to thetime delay information.

In a second aspect of the fifth embodiment, processing comprisesutilizing the sensor data from the second analyte sensor to assessperformance of the first analyte sensor.

In a third aspect of the fifth embodiment, the first analyte sensor is atranscutaneous sensor.

In a fourth aspect of the fifth embodiment, the first analyte sensor isa wholly implantable sensor. In one embodiment of this aspect, thesecond analyte sensor is a transcutaneous sensor.

In a fifth aspect of the fifth embodiment, the second analyte sensor isa transcutaneous sensor.

In a sixth aspect of the fifth embodiment, the second analyte sensor isa wholly implantable sensor.

In a seventh aspect of the fifth embodiment, the processing comprisescalibrating the first analyte sensor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic of a system with one receiver where one sensor isused to calibrate another sensor.

FIG. 1B is a schematic of a system with more than one receiver where onesensor is used to calibrate another sensor.

FIG. 1C is a schematic of a system that uses sensor data from a shortterm sensor to calibrate sensor data from a long term sensor.

FIG. 1D is a schematic of a system that uses two or more short termsensors to calibrate short term sensors and/or long term sensors.

FIG. 1E is a schematic of a system that uses sensor data from a longterm sensor to calibrate sensor data from another long term sensor.

FIG. 1F is a schematic of a system that uses sensor data from a shortterm sensor to calibrate sensor data from another short term sensor.

FIG. 2 is a perspective view of a transcutaneous analyte sensor system,including an applicator, a mounting unit, and an electronics unit.

FIG. 3 is a perspective view of a mounting unit, including theelectronics unit in its functional position.

FIG. 4 is an exploded perspective view of a mounting unit, showing itsindividual components.

FIG. 5A is an exploded perspective view of a contact subassembly,showing its individual components.

FIG. 5B is a perspective view of an alternative contact configuration.

FIG. 5C is a perspective view of another alternative contactconfiguration.

FIGS. 5D to 5H are schematic cross-sectional views of a portion of thecontact subassembly; namely, a variety of embodiments illustratingalternative sealing member configurations.

FIG. 6A is an expanded cutaway view of a proximal portion of a sensor.

FIG. 6B is an expanded cutaway view of a distal portion of a sensor.

FIG. 6C is a cross-sectional view through the sensor of FIG. 5B on lineC-C, showing an exposed electroactive surface of a working electrodesurrounded by a membrane system.

FIG. 7 is an exploded side view of an applicator, showing the componentsthat facilitate sensor insertion and subsequent needle retraction.

FIGS. 8A to 8D are schematic side cross-sectional views that illustrateapplicator components and their cooperating relationships.

FIG. 9A is a perspective view of an applicator and mounting unit in oneembodiment including a safety latch mechanism.

FIG. 9B is a side view of an applicator matingly engaged to a mountingunit in one embodiment, prior to sensor insertion.

FIG. 9C is a side view of a mounting unit and applicator depicted in theembodiment of FIG. 9B, after the plunger subassembly has been pushed,extending the needle and sensor from the mounting unit.

FIG. 9D is a side view of a mounting unit and applicator depicted in theembodiment of FIG. 9B, after the guide tube subassembly has beenretracted, retracting the needle back into the applicator.

FIG. 9E is a perspective view of an applicator, in an alternativeembodiment, matingly engaged to the mounting unit after to sensorinsertion.

FIG. 9F is a perspective view of the mounting unit and applicator, asdepicted in the alternative embodiment of FIG. 9E, matingly engagedwhile the electronics unit is slidingly inserted into the mounting unit.

FIG. 9G is a perspective view of the electronics unit, as depicted inthe alternative embodiment of FIG. 9E, matingly engaged to the mountingunit after the applicator has been released.

FIGS. 9H and 9I are comparative top views of the sensor system shown inthe alternative embodiment illustrated in FIGS. 9E to 9G as compared tothe embodiments illustrated in FIGS. 9B to 9D.

FIGS. 10A to 10C are side views of a sensor system adhered with anextensible adhesive pad in one embodiment. The figures illustrate thesystem prior to and during initial and continued release of the mountingunit from the host's skin.

FIGS. 11A and 11B are perspective and side cross-sectional views,respectively, of a sensor system showing the mounting unit immediatelyfollowing sensor insertion and release of the applicator from themounting unit.

FIGS. 12A and 12B are perspective and side cross-sectional views,respectively, of a sensor system showing the mounting unit afterpivoting the contact subassembly to its functional position.

FIGS. 13A to 13C are perspective and side views, respectively, of thesensor system showing the sensor, mounting unit, and electronics unit intheir functional positions.

FIG. 14 is a perspective view of a sensor system wirelesslycommunicating with a receiver.

FIGS. 15A and 15B are perspective views of a receiver in one preferredembodiment, wherein the receiver is provided with a docking station forreceiving and holding the electronics unit (from the sensor assembly)when not in use.

FIG. 16 is an exploded perspective view of one exemplary embodiment of acontinuous glucose sensor

FIG. 17 is a block diagram that illustrates electronics associated witha sensor system.

FIG. 18 is a graph that illustrates data smoothing of a raw data signalin one embodiment.

FIG. 19A illustrates a first embodiment wherein the receiver shows anumeric representation of the estimated analyte value on its userinterface, which is described in more detail elsewhere herein.

FIG. 19B illustrates a second embodiment wherein the receiver shows anestimated glucose value and one hour of historical trend data on itsuser interface, which is described in more detail elsewhere herein.

FIG. 19C illustrates a third embodiment wherein the receiver shows anestimated glucose value and three hours of historical trend data on itsuser interface, which is described in more detail elsewhere herein.

FIG. 19D illustrates a fourth embodiment wherein the receiver shows anestimated glucose value and nine hours of historical trend data on itsuser interface, which is described in more detail elsewhere herein.

FIG. 20A is a block diagram that illustrates a configuration of amedical device including a continuous analyte sensor, a receiver, and anexternal device.

FIGS. 20B to 20D are illustrations of receiver liquid crystal displaysshowing embodiments of screen displays.

FIG. 21 is a flow chart that illustrates the initial calibration anddata output of the sensor data in one embodiment.

FIG. 22A is a graph that illustrates a regression performed on acalibration set to obtain a conversion function in one exemplaryembodiment.

FIG. 22B is a graph that illustrates one example of using priorinformation for slope and baseline.

FIG. 22C is a slope-baseline graph illustrating one example of usingprior distribution information for determining a calibration slope andbaseline.

FIG. 23 is a graph of two data pairs on a Clarke Error Grid toillustrate the evaluation of clinical acceptability in one exemplaryembodiment.

FIG. 24 is a flow chart that illustrates the process of evaluation ofcalibration data for best calibration based on inclusion criteria ofmatched data pairs in one embodiment.

FIG. 25 is a flow chart that illustrates the process of evaluating thequality of the calibration in one embodiment.

FIG. 26A and FIG. 26B are graphs that illustrate an evaluation of thequality of calibration based on data association in one exemplaryembodiment using a correlation coefficient.

FIG. 27 is a graph that illustrates an exemplary relationship betweenin-vitro and in-vivo sensitivity.

FIG. 28 is a graphical representation showing sensor data resulting fromapplying the in-vitro/in-vivo relationship of FIG. 27 to a substantiallycontinuous analyte sensor and showing blood glucose readings over aperiod of time, from an exemplary application.

FIG. 29 is a graphical representation of glucose data from an analytesensor and blood glucose readings over a time period from an exemplaryapplication.

FIG. 30 is a graphical representation of sensor data from anun-calibrated long term sensor and a calibrated short term sensoremployed on the same host.

FIG. 31 is a graphical representation of sensor data from a long termsensor, that was calibrated using the short term sensor data shown inFIG. 30, prospectively applied and compared to reference glucosemeasurements.

FIG. 32 is a graphical representation of sensor data from a short termsensor calibrated by sensor data from another short term sensor.

FIG. 33 is a graphical representation of a regression used to calibratesensor data shown in FIG. 32.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

The following description and examples illustrate a preferred embodimentof the present invention in detail. Those of skill in the art willrecognize that there are numerous variations and modifications of thisinvention that are encompassed by its scope. Accordingly, thedescription of a preferred embodiment should not be deemed to limit thescope of the present invention.

Definitions

In order to facilitate an understanding of the disclosed invention, anumber of terms are defined below.

The term “A/D Converter” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to hardware that converts analogsignals into digital signals.

The term “analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substance or chemical constituent in abiological fluid (for example, blood, interstitial fluid, cerebralspinal fluid, lymph fluid or urine) that can be analyzed. Analytes caninclude naturally occurring substances, artificial substances,metabolites, and/or reaction products. In some embodiments, the analytefor measurement by the sensing regions, devices, and methods is glucose.However, other analytes are contemplated as well, including but notlimited to acarboxyprothrombin; acylcarnitine; adenine phosphoribosyltransferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acidprofiles (arginine (Krebs cycle), histidine/urocanic acid, homocysteine,phenylalanine/tyrosine, tryptophan); andrenostenedione; antipyrine;arabinitol enantiomers; arginase; benzoylecgonine (cocaine);biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4;ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol;cholinesterase; conjugated 1-β hydroxy-cholic acid; cortisol; creatinekinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylatorpolymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cysticfibrosis, Duchenne/Becker muscular dystrophy, glucose-6-phosphatedehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D,hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis Bvirus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD,RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol);desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanusantitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D;fatty acids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte can be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body can also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC),homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and5-hydroxyindoleacetic acid (FHIAA).

The term “analyte sensor” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to any mechanism (e.g.,enzymatic or non-enzymatic) by which analyte can be quantified. Forexample, some embodiments utilize a membrane that contains glucoseoxidase that catalyzes the conversion of oxygen and glucose to hydrogenperoxide and gluconate:

Glucose+O₂→Gluconate+H₂O₂

Because for each glucose molecule metabolized, there is a proportionalchange in the co-reactant O₂ and the product H₂O₂, one can use anelectrode to monitor the current change in either the co-reactant or theproduct to determine glucose concentration.

The term “biointerface membrane” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a permeable membrane that canbe comprised of two or more domains and constructed of materials of afew microns thickness or more, which can be placed over the sensor bodyto keep host cells (e.g., macrophages) from gaining proximity to, andthereby damaging, the sensing membrane or forming a barrier cell layerand interfering with the transport of analyte across the tissue-deviceinterface. The term “exit-site” as used herein is a broad term and isused in its ordinary sense, including, without limitation, the areawhere a medical device (for example, a sensor and/or needle) exits fromthe host's body.

The term “Clarke Error Grid” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an error grid analysis, whichevaluates the clinical significance of the difference between areference glucose value and a sensor generated glucose value, takinginto account (1) the value of the reference glucose measurement; (2) thevalue of the sensor glucose measurement; (3) the relative differencebetween the two values; and (4) the clinical significance of thisdifference. See Clarke et al., “Evaluating Clinical Accuracy of Systemsfor Self-Monitoring of Blood Glucose”, Diabetes Care, Volume 10, Number5, September-October 1987.

The term “clinical acceptability” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to determination of the risk ofinaccuracies to a patient. Clinical acceptability considers a deviationbetween time corresponding glucose measurements (e.g., data from aglucose sensor and data from a reference glucose monitor) and the risk(e.g., to the decision making of a diabetic patient) associated withthat deviation based on the glucose value indicated by the sensor and/orreference data. One example of clinical acceptability can be 85% of agiven set of measured analyte values within the “A” and “B” region of astandard Clarke Error Grid when the sensor measurements are compared toa standard reference measurement.

The term “concordant” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to being in agreement or harmony, and/or freefrom discord.

The term “congruence” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the quality or state of agreeing,coinciding, or being concordant. In one example, congruence can bedetermined using rank correlation.

The term “Consensus Error Grid” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an error grid analysis thatassigns a specific level of clinical risk to any possible error betweentwo time corresponding glucose measurements. The Consensus Error Grid isdivided into zones signifying the degree of risk posed by the deviation.See Parkes et al., “A New Consensus Error Grid to Evaluate the ClinicalSignificance of Inaccuracies in the Measurement of Blood Glucose”,Diabetes Care, Volume 23, Number 8, August 2000.

The phrase “continuous” as it relates to analyte sensing or an analytesensor and as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to continuously, continually, and/orintermittently (regularly or irregularly) monitoring an analyteconcentration, performed, for example, about every 1 second to 20minutes.

The term “counts” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a unit of measurement of a digital signal.In one example, a raw data signal measured in counts is directly relatedto a voltage (converted by an A/D converter), which is directly relatedto current.

The terms “data association” and “data association function” as usedherein are broad terms, and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and are not to belimited to a special or customized meaning), and refer withoutlimitation to a statistical analysis of data and particularly itscorrelation to, or deviation from, from a particular curve. A dataassociation function is used to show data association. For example, thedata that forms that calibration set as described herein can be analyzedmathematically to determine its correlation to, or deviation from, acurve (e.g., line or set of lines) that defines the conversion function;this correlation or deviation is the data association. A dataassociation function is used to determine data association. Examples ofdata association functions include, but are not limited to, linearregression, non-linear mapping/regression, rank (e.g., non-parametric)correlation, least mean square fit, mean absolute deviation (MAD), meanabsolute relative difference. In one such example, the correlationcoefficient of linear regression is indicative of the amount of dataassociation of the calibration set that forms the conversion function,and thus the quality of the calibration.

The term “domain” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to regions of the biointerface membrane thatcan be layers, uniform or non-uniform gradients (for example,anisotropic) or provided as portions of the membrane.

The term “EEPROM” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to electrically erasable programmableread-only memory, which is user-modifiable read-only memory (ROM) thatcan be erased and reprogrammed (e.g., written to) repeatedly through theapplication of higher than normal electrical voltage.

The term “electrochemically reactive surface” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to the surface of anelectrode where an electrochemical reaction takes place. In one example,a working electrode measures hydrogen peroxide produced by the enzymecatalyzed reaction of the analyte being detected reacts creating anelectric current (for example, detection of glucose analyte utilizingglucose oxidase produces H₂O₂ as a by product, H₂O₂ reacts with thesurface of the working electrode producing two protons (2H⁺), twoelectrons (2e⁻) and one molecule of oxygen (O₂) which produces theelectronic current being detected). In the case of the counterelectrode, a reducible species, for example, O₂ is reduced at theelectrode surface in order to balance the current being generated by theworking electrode.

The term “electronic connection” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to any electronic connectionknown to those in the art that can be utilized to interface the sensorhead electrodes with the electronic circuitry of a device such asmechanical (e.g., pin and socket) or soldered.

The term “electronic connection” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to any electronic connectionknown to those in the art that can be utilized to interface the sensingregion electrodes with the electronic circuitry of a device such asmechanical (for example, pin and socket) or soldered.

The term “ex vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the portion of the device(for example, sensor) adapted to remain and/or exist outside the livingbody of a host.

The term “host” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to mammals, particularly humans.

The term “in vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the portion of the device(for example, sensor) adapted for insertion and/or existence within theliving body of a host.

The term “jitter” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to uncertainty or variability of waveformtiming, which can be cause by ubiquitous noise caused by a circuitand/or environmental effects; jitter can be seen in amplitude, phasetiming, or the width of the signal pulse.

The term “long term” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the lifespan of an analyte sensor. Forexample, the term “long term analyte sensor” is used herein relative tothe term “short term analyte sensor” and designates an analyte sensorwith a lifespan that is more than the lifespan of the short term analytesensor. For example, a short term analyte sensor can have a lifespan ofabout less than about an hour to about three weeks, and a long termanalyte sensor has a corresponding lifespan of longer than three weeks.

The term “matched data pairs” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to reference data (e.g., one ormore reference analyte data points) matched with substantially timecorresponding sensor data (e.g., one or more sensor data points).

The term “microprocessor” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a computer system orprocessor designed to perform arithmetic and logic operations usinglogic circuitry that responds to and processes the basic instructionsthat drive a computer.

The phrase “noncontinuous” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to single point analytemonitoring of an analyte concentration, for example, performed usingblood glucose meters (e.g., using finger stick blood samples) andoptical measuring techniques (e.g., near infrared spectroscopy, infraredspectroscopy, raman spectroscopy, photoacoustic spectroscopy, scatterand polarization changes), etc.

The terms “operable connection,” “operably connected,” and “operablylinked” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefer without limitation to one or more components being linked toanother component(s) in a manner that allows transmission of signalsbetween the components, e.g., wired or wirelessly. For example, one ormore electrodes can be used to detect the amount of analyte in a sampleand convert that information into a signal; the signal can then betransmitted to an electronic circuit means. In this case, the electrodeis “operably linked” to the electronic circuitry.

The term “oxygen antenna domain” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a domain composed of amaterial that has higher oxygen solubility than aqueous media so that itconcentrates oxygen from the biological fluid surrounding thebiointerface membrane. The domain can then act as an oxygen reservoirduring times of minimal oxygen need and has the capacity to provide ondemand a higher oxygen gradient to facilitate oxygen transport acrossthe membrane. This enhances function in the enzyme reaction domain andat the counter electrode surface when glucose conversion to hydrogenperoxide in the enzyme domain consumes oxygen from the surroundingdomains. Thus, this ability of the oxygen antenna domain to apply ahigher flux of oxygen to critical domains when needed improves overallsensor function.

The term “quality of calibration” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the statistical associationof matched data pairs in the calibration set used to create theconversion function. For example, an R-value can be calculated for acalibration set to determine its statistical data association, whereinan R-value greater than 0.79 determines a statistically acceptablecalibration quality, while an R-value less than 0.79 determinesstatistically unacceptable calibration quality.

The term “raw data signal” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an analog or digital signaldirectly related to the measured analyte from the analyte sensor. In oneexample, the raw data signal is digital data in “counts” converted by anA/D converter from an analog signal (e.g., voltage or amps)representative of an analyte concentration.

The term “RF transceiver” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a radio frequency transmitterand/or receiver for transmitting and/or receiving signals.

The term “R-value” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to one conventional way of summarizing thecorrelation of data; that is, a statement of what residuals (e.g., rootmean square deviations) are to be expected if the data are fitted to astraight line by the a regression.

The term “sensing membrane” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a permeable or semi-permeablemembrane that can be comprised of two or more domains and constructed ofmaterials of a few microns thickness or more, which are permeable tooxygen and can or can not be permeable to an analyte of interest. In oneexample, the sensing membrane comprises an immobilized glucose oxidaseenzyme, which enables an electrochemical reaction to occur to measure aconcentration of glucose.

The term “sensing region” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the region of a monitoringdevice responsible for the detection of a particular analyte. Thesensing region generally comprises a non-conductive body, a workingelectrode (anode), a reference electrode (optional), and/or a counterelectrode (cathode) passing through and secured within the body formingelectrochemically reactive surfaces on the body and an electronicconnective means at another location on the body, and a multi-domainmembrane affixed to the body and covering the electrochemically reactivesurface.

The term “sensor head” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the region of a monitoringdevice responsible for the detection of a particular analyte. In oneexample, a sensor head comprises a non-conductive body, a workingelectrode (anode), a reference electrode and a counter electrode(cathode) passing through and secured within the body forming anelectrochemically reactive surface at one location on the body and anelectronic connective means at another location on the body, and asensing membrane affixed to the body and covering the electrochemicallyreactive surface. The counter electrode has a greater electrochemicallyreactive surface area than the working electrode. During generaloperation of the sensor a biological sample (e.g., blood or interstitialfluid) or a portion thereof contacts (directly or after passage throughone or more membranes or domains) an enzyme (e.g., glucose oxidase); thereaction of the biological sample (or portion thereof) results in theformation of reaction products that allow a determination of the analyte(e.g., glucose) level in the biological sample. In some embodiments, thesensing membrane further comprises an enzyme domain (e.g., and enzymelayer), and an electrolyte phase (e.g., a free-flowing liquid phasecomprising an electrolyte-containing fluid described further below).

The term “short term” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the lifespan of an analyte sensor. Forexample, the term “short term analyte sensor” is used herein relative tothe term “long term analyte sensor” and designates an analyte sensorwith a lifespan less than the lifespan of a long term analyte sensor.For example, a short term analyte sensor can have a lifespan of lessthan an hour to about three weeks, and a long term analyte sensor has acorresponding lifespan of longer than three weeks.

The term “SRAM” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to static random access memory (RAM) thatretains data bits in its memory as long as power is being supplied.

The term “substantially” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to being largely but notnecessarily wholly that which is specified.

In the disclosure which follows, the following abbreviations apply: Eqand Eqs (equivalents); mEq (milliequivalents); M (molar); mM(millimolar) μM (micromolar); N (Normal); mol (moles); mmol(millimoles); μmol (micromoles); nmol (nanomoles); g (grams); mg(milligrams); μg (micrograms); Kg (kilograms); L (liters); mL(milliliters); dL (deciliters); μL (microliters); cm (centimeters); mm(millimeters); μm (micrometers); nm (nanometers); h and hr (hours); min.(minutes); s and sec. (seconds); ° C. (degrees Centigrade).

Overview

Some of the aspects of the invention relate to calibrating asubstantially continuous analyte sensor (e.g., a subcutaneous,transdermal (e.g., transcutaneous), or intravascular device) usingsensor data from another substantially continuous analyte sensor. Theanalyte sensor can be any type of sensor that measures a concentrationof an analyte of interest or a substance indicative of the concentrationor presence of the analyte. The analyte sensors can be short or longterm sensors. For example, in some embodiments, the sensor data from ashort term substantially continuous analyte sensor is used to calibratethe sensor data from another short term substantially continuous analytesensor. In another embodiment, the sensor data from a short termsubstantially continuous analyte sensor is used to calibrate the sensordata from a long term substantially continuous analyte sensor. In oneembodiment, the sensor data from a long term substantially continuousanalyte sensor is used to calibrate the sensor data from another longterm substantially continuous analyte sensor. In other embodiments, thesensor data from a long term substantially continuous analyte sensor isused to calibrate the sensor data from a short term substantiallycontinuous analyte sensor. The analyte sensors can use any method ofanalyte-sensing, including enzymatic, chemical, physical,electrochemical, spectrophotometric, polarimetric, calorimetric,radiometric, or the like.

FIG. 1A is a schematic illustrating one embodiment of a system wheredata from one is used to calibrate another sensor. The system includestwo substantially continuous analyte sensors, sensor_(A) and sensor_(B),configured to provide sensor data to a receiver. Sensor_(A) andsensor_(B) can be any substantially continuous analyte sensors capableof determining the level of an analyte in the body, for example glucose,oxygen, lactase, insulin, hormones, cholesterol, medicaments, viruses,or the like. Sensor_(A) and sensor_(B) can be short term or long termsensors. Sensor_(A) and sensor_(B) detect information relating to ananalyte in the host 6 and transmit the information (e.g., sensor data)to the receiver 8. The transmission of the sensor data can be through awire or wireless communication channel. In this embodiment, sensor_(A)and sensor_(B) measure the same analyte (e.g., glucose). If there iscorrelation and/or a predictive relationship between the sensor datafrom sensor_(A) and sensor_(B), the sensor data from one analyte sensorcan be used to calibrate the sensor data from the other analyte sensor.If sensor_(A) and sensor_(B) measure two different analytes but there iscorrelation and/or predictive behavior between the sensor data for thetwo different analytes, the sensor data from one analyte sensor can beused to calibrate the sensor data from the other analyte sensor. In suchan embodiment, the receiver is configured to receive the sensor datafrom both sensors, process the data, and calibrate one of the sensors,using e.g., data processing and calibration techniques as describedherein and other suitable sensor calibration techniques.

FIG. 1B is a schematic illustrating another embodiment of a system wheredata from one sensor is used to calibrate another sensor. Thisembodiment also includes two substantially continuous analyte sensors,sensor_(c) and sensor_(D), that detect information relating to ananalyte in the host 6 and transmit the information to a receiver.Sensor_(A) and sensor_(B) can be short term or long term sensors. Inthis embodiment, sensor_(C) transmits sensor data to receiver_(A) andsensor_(D) transmits sensor data to receiver_(B). Receiver_(A) andreceiver_(B) are configured to communicate information with each other(e.g., analyte measurement information, corresponding timestamp ofanalyte measurement, etc.) so that the sensor data from one sensor canbe used to calibrate the sensor data from the other. Here, for example,so long as the receivers can communicate, the communication protocol,content, and data format for one sensor and its receiver can bedifferent than for the other sensor and its receiver. Some of theembodiments described and illustrated herein, e.g., FIGS. 1C and 1E,include one receiver that can receive data from one or more sensors.However, in such embodiments, additional receivers can be employed(e.g., one receiver for each sensor).

FIG. 1C is a schematic illustrating an embodiment of a system thatcalibrates a long term sensor using sensor data from a short termsensor. A long term analyte sensor can have an initial instability timeperiod during which it is unstable for environmental, physiological, orother reasons. For example, for a long term analyte sensor implantedsubcutaneously, its stabilization can be dependent upon the maturity ofthe tissue ingrowth around and within the sensor (see, e.g., U.S.Publication No. US-2005-0112169-A1). Accordingly, determination ofsensor stability can include waiting a time period (e.g., an implantablesensor is known to require a time period for tissue, and a transdermal(e.g., transcutaneous) sensor is known to require time to equilibratethe sensor with the user's tissue); in some embodiments, this waitingperiod is from about one minute to about three weeks. This waitingperiod can be predetermined by prior testing the sensor under similarconditions, and/or by analysis of the data from the sensor to determinethat the sensor is stable. In this embodiment, the short term sensormeasures the analyte and provides data to a receiver during the waitingperiod. Once the long term sensor is deemed to be stable, the data fromthe long term sensor requires calibration to provide an accurate value.Where the sensor data from the short term sensor has a correlative orpredictive relationship with the sensor data from the long term sensor,the data from the short term sensor can be used to calibrate the longterm sensor. Calibration of the sensor data from a long term sensorusing sensor data provided by the short term sensor facilitates the useof the long term sensor data sooner and/or reduces or obviates the needto calibrate the long term sensor with single point calibrationtechniques, e.g., using finger stick blood samples, optical measuringtechniques etc.

The sensor data from a long term sensor can change over time, due to,for example, a decrease in its sensitivity. In one embodiment, a longterm sensor can be re-calibrated by employing a short term sensor on thesame host as the long term sensor and then using the sensor data fromthe short term sensor to calibrate the sensor data from the long termsensor. For example, on a host having a long term (e.g., whollyimplantable) sensor, a substantially continuous short term (e.g.,transcutaneous) analyte sensor can also be employed. A short term sensortaking a measurement every five minutes provides sensor data for 288measurements in a day. The receiver translates the short sensor data toestimate analyte values, which are used to re-calibrate the long termsensor using e.g., data processing techniques described herein,including data processing techniques described in reference to FIGS. 16and 17. As another example, a short term sensor can be used to troubleshoot a long term sensor, for example, when the long term sensor iswholly implanted in the host and experiences malfunctioning. In such asituation, a short term sensor can be inserted into the host (e.g., atranscutaneous sensor) and the data compared to that of the long termsensor (e.g., wholly implantable sensor) to diagnose potential problemswith the long term sensor, for example, signal noise due to oxygendeficiencies or enzyme deficiency. In alternative embodiments, shortand/or long term sensors can be used to diagnose problems in other shortand/or long term sensors.

FIG. 1D is a schematic illustrating an embodiment of a system thatcalibrates a long term sensor using sensor data from one or more shortterm sensors. In certain circumstances a single short term sensor is notable to provide sensor data for the entire waiting period of the longterm sensor. For example, the lifespan of the short term sensor may beless than the requisite waiting period. Accordingly, the use of two ormore short term sensors can be used to provide sensor data for theentire waiting period for a long term sensor if the waiting period isgreater than three days.

In FIG. 1D, two or more short term sensors are used to provide analytemeasurements during the waiting period of a long term sensor. Forexample, a short term sensor A is used to provide analyte measurementsto a receiver for its usable lifespan. Prior to the end of the lifespanof sensor A, short term sensor B is employed to also provide analytemeasurements to a receiver for the host 6, so that sensor A and sensor Bare both providing sensor data during an overlapping time period. If thewaiting period of the long term sensor is longer than the period thatcan be covered by sensor A and B, another short-term sensor can beemployed prior to the end of the lifespan of sensor B. Substitution ofshort term sensors in an overlapping manner can be repeated until theexpiration of the waiting period. Once the long term sensor is stable,it can be calibrated using sensor data from one or more of the shortterm sensors. Alternatively, one or more short-term sensor may beimplanted near the time when the long term sensor is expected to startworking rather than having the short term sensors implanted during theentire waiting period of the long term sensor.

In one embodiment, where two or more short term sensors are used on thesame host, the sensor data from one short term sensor can be used tocalibrate the other short term sensor. For example, in theabove-described embodiment, the receiver can use the sensor data fromsensor A to calibrate the sensor data from B, which can be used tocalibrate each successive short term sensor employed on the host 6.

In some embodiments, one or more of the short term sensors arecalibrated in-vitro, e.g., by a benchtop calibration process thatpredetermines the information particular to the sensor. In suchembodiments, the series of short term sensors need not overlap eachother for calibration purposes. In one example, a benchtop calibratedshort term sensor can be used to calibrate a long term implantableglucose sensor so that manual glucose measurements (SMBG) are notneeded. According to one embodiment of a sensor, the sensing mechanismof an enzyme-electrode based glucose sensor depends on two phenomenathat are linear with glucose concentration: (1) diffusion of glucosethrough a membrane system situated between interstitial fluid and theelectrode surface, and (2) an enzymatic reaction within the membranesystem. Because of this linearity, calibration/recalibration of thesensor consists of solving the line

y=mx+b

where y denotes the sensor signal (in units of A/D counts), x theestimated glucose concentration (mg/dl), m the sensor sensitivity toglucose (counts/mg/dl), and b the baseline signal (counts).

Typically, calibration requires at least two independent, pairedmeasurements (x₁, y_(i); x₂, y₂) to solve for m and b and thus allowglucose estimation when only the sensor signal, y is available. However,if prior information is available for m and/or b, then calibration canoccur with fewer paired measurements. In one embodiment of asemi-benchtop calibration technique, prior information (e.g., benchtoptests) determine the sensitivity of the sensor and/or the baselinesignal of the sensor by analyzing sensor data from measurements taken bythe sensor of a controlled solution (e.g., prior to inserting thesensor). If there exists a predictive relationship between benchtopsensor parameters and in-vivo parameters, then this information can beused by the calibration procedure. For example, if a predictiverelationship exists between benchtop sensitivity and in-vivosensitivity, m f(m_(benchtop)), then the predicted m can be used, alongwith a single matched pair, to solve for b (b=y−mx, semi-benchtopcalibration). If in addition, b can be assumed to be 0, for example witha biointerface electrode configuration, then both m and b are known apriori, matched pairs are not needed for calibration, and the sensor canbe completely benchtop calibrated.

Other methods for using information obtained prior to sensor insertionin sensor calibration are discussed in more detail elsewhere herein.

In some embodiments, the long term sensor can be benchtop calibrated andthen once implanted, the calibration of the data from the long termsensor can be adjusted using additional reference data, for example,reference data from a short term sensor. Typically for a long termsensor, as its biointerface matures, its m and b change. This change (a10% change in signal amplitude, for example) over a period of time (twoweeks) can be solved for with periodic use of a short term sensor asfollows: a user implanted with a long term sensor inserts a short termsensor, the short term sensor glucose values (if collected at 5 minintervals, there are 288 per day) are used as the reference values, x,to which the long term sensor values, y, can be calibrated. Thisprocedure would allow for accurate estimates of m, b, and time-lag(assuming the time-lag of the short term sensor signal relative to bloodglucose). Accordingly, reference data from a short term glucose sensorcan be used in the initial calibration process described herein andshown in FIG. 21, and the update calibration process described hereinand shown in FIG. 24.

In the embodiment illustrated in FIG. 1E, the sensor data for one longterm sensor is used to calibrate the sensor data from another long termsensor. Long term sensor A can be employed on the host 6 and calibratedusing, e.g., data from a short term sensor, a long term sensor, oranother calibration technique. Prior to the end of the lifespan of longterm sensor A, long term sensor B can be implanted into the host 6. Oncelong term sensor B is stable, sensor data from long term sensor A can beused to calibrate the sensor data from long tem sensor B. Thiscalibration process can be repeated for additional long term sensorsemployed on host 6, so that a series of long term sensors can beemployed, with the sensor data from each newly employed sensor beingcalibrated using sensor data from the previously employed long termsensor. By this means, a patient can have continuity of data while onlyundergoing one procedure for each long term implant, for example, onceper year. In one example, Sensor A is implanted at time 0. After 11months, Sensor B is implanted, and Sensor A is left in place. During thenext month, Sensor B starts up and is calibrated using data from sensorA. At time 23 months, Sensor C is implanted and Sensor A is removed.Sensor B is used to calibrate Sensor C, and so forth for as long as thepatient wishes to continue placing new sensors. Other time frames ofsensor implantation and overlap are also possible.

FIG. 1F is a schematic illustrating an embodiment of a system thatcalibrates a short term sensor using sensor data from a short termsensor. It is known that some transdermal (e.g., transcutaneous) sensorsrequire time to equilibrate the sensor with the user's tissue (e.g., dueto electrochemical break-in). For example, when a first short termsensor's lifespan is nearing its end, a second short term sensor can beimplanted into the user's tissue (e.g., at another location) to allowthat sensor to equilibrate while the first short term sensor is stillproviding data. In addition to providing data during the equilibrationtime of the second short term sensor (thereby allowing data continuity),the first short term sensor can provide additional data, includingcalibration information, time lag information, drift information, andthe like, to the second short term sensor to increase its intelligenceand enhance its performance.

The sensors of the preferred embodiments can be employed sequentiallyand/or simultaneously (e.g., redundant sensors). For example, one ormore short or long term sensors can be used simultaneously in order tocompare, trouble-shoot, and/or provide increased data to the host. Inone situation, by providing at least two redundant sensors, transientproblems experienced by one sensor can be negated by the use of theother sensor.

An analyte sensor uses any known method, including invasive, minimallyinvasive, and non-invasive sensing techniques, to provide an outputsignal indicative of the concentration of the analyte of interest. Theoutput signal is typically a raw signal that is used to provide a valuethat can be used for calibrating another analyte sensor or an analytesensor used in another application. Appropriate smoothing, calibration,and evaluation methods can be applied to the raw signal and/or system asa whole to provide relevant and acceptable analyte data for calibratinganother analyte sensor or the same analyte sensor used in anotherapplication.

The analyte sensor(s) useful with the preferred embodiments can be anydevice capable of measuring the concentration of an analyte of interest.One exemplary embodiment is described below, which calibrates a longterm implantable glucose sensor based on data from a short termimplantable glucose sensor. However, it can be understood that thedevices and methods described herein can be applied to any devicecapable of detecting a concentration of analyte of and providing anoutput signal that represents the concentration of the analyte for usein calibrating another sensor.

Short Term Sensor

In one embodiment, the short term sensors for use as described hereininclude a transcutaneous analyte sensor system that includes anapplicator for inserting the transcutaneous (transdermal) analyte sensorunder a host's skin. The sensor system includes a sensor for sensing theanalyte, wherein the sensor is associated with a mounting unit adaptedfor mounting on the skin of the host. The mounting unit houses theelectronics unit associated with the sensor and is adapted for fasteningto the host's skin. In certain embodiments, the system further includesa receiver for receiving and/or processing sensor data.

FIG. 2 is a perspective view of a transcutaneous analyte sensor system10. In the preferred embodiment of a system as depicted in FIG. 2, thesensor includes an applicator 12, a mounting unit 14, and an electronicsunit 16. The system can further include a receiver 158, such as isdescribed in more detail with reference to FIG. 14.

The mounting unit (housing) 14 includes a base 24 adapted for mountingon the skin of a host, a sensor adapted for transdermal (e.g.,transcutaneous) insertion through the skin of a host (see FIG. 5A), andone or more contacts 28 configured to provide secure electrical contactbetween the sensor and the electronics unit 16. The mounting unit 14 isdesigned to maintain the integrity of the sensor in the host so as toreduce or eliminate translation of motion between the mounting unit, thehost, and/or the sensor.

In one embodiment, an applicator 12 is provided for inserting the sensor32 through the host's skin at the appropriate insertion angle with theaid of a needle (see FIGS. 7 through 9), and for subsequent removal ofthe needle using a continuous push-pull action. Preferably, theapplicator comprises an applicator body 18 that guides the applicatorcomponents (see FIGS. 7 through 9) and includes an applicator body base60 configured to mate with the mounting unit 14 during insertion of thesensor into the host. The mate between the applicator body base 60 andthe mounting unit 14 can use any known mating configuration, forexample, a snap-fit, a press-fit, an interference-fit, or the like, todiscourage separation during use. One or more release latches 30 enablerelease of the applicator body base 60, for example, when the applicatorbody base 60 is snap fit into the mounting unit 14.

The electronics unit 16 includes hardware, firmware, and/or softwarethat enable measurement of levels of the analyte via the sensor. Forexample, the electronics unit 16 can comprise a potentiostat, a powersource for providing power to the sensor, other components useful forsignal processing, and preferably an RF module for transmitting datafrom the electronics unit 16 to a receiver. Electronics can be affixedto a printed circuit board (PCB), or the like, and can take a variety offorms. For example, the electronics can take the form of an integratedcircuit (IC), such as an Application-Specific Integrated Circuit (ASIC),a microcontroller, or a processor. Preferably, electronics unit 16houses the sensor electronics, which comprise systems and methods forprocessing sensor analyte data. Examples of systems and methods forprocessing sensor analyte data are described in more detail in U.S.Publication No. US-2005-0027463-A1.

After insertion of the sensor using the applicator 12, and subsequentrelease of the applicator 12 from the mounting unit 14 (see FIGS. 9B to9D), the electronics unit 16 is configured to releasably mate with themounting unit 14 in a manner similar to that described above withreference to the applicator body base 60. The electronics unit 16includes contacts on its backside (not shown) configured to electricallyconnect with the contacts 28, such as are described in more detail withreference to FIGS. 3 through 5. In one embodiment, the electronics unit16 is configured with programming, for example initialization,calibration reset, failure testing, or the like, each time it isinitially inserted into the mounting unit 14 and/or each time itinitially communicates with the sensor 32.

Mounting Unit

FIG. 3 is a perspective view of a sensor system of a preferredembodiment, shown in its functional position, including a mounting unitand an electronics unit matingly engaged therein. FIGS. 13A to 13Cillustrate the sensor is its functional position for measurement of ananalyte concentration in a host.

In preferred embodiments, the mounting unit 14, also referred to as ahousing, comprises a base 24 adapted for fastening to a host's skin. Thebase can be formed from a variety of hard or soft materials, andpreferably comprises a low profile for minimizing protrusion of thedevice from the host during use. In some embodiments, the base 24 isformed at least partially from a flexible material, which is believed toprovide numerous advantages over conventional transcutaneous sensors,which, unfortunately, can suffer from motion-related artifactsassociated with the host's movement when the host is using the device.For example, when a transcutaneous analyte sensor is inserted into thehost, various movements of the sensor (for example, relative movementbetween the in vivo portion and the ex vivo portion, movement of theskin, and/or movement within the host (dermis or subcutaneous)) createstresses on the device and can produce noise in the sensor signal. It isbelieved that even small movements of the skin can translate todiscomfort and/or motion-related artifact, which can be reduced orobviated by a flexible or articulated base. Thus, by providingflexibility and/or articulation of the device against the host's skin,better conformity of the sensor system 10 to the regular use andmovements of the host can be achieved. Flexibility or articulation isbelieved to increase adhesion (with the use of an adhesive pad) of themounting unit 14 onto the skin, thereby decreasing motion-relatedartifact that can otherwise translate from the host's movements andreduced sensor performance.

FIG. 4 is an exploded perspective view of a sensor system of a preferredembodiment, showing a mounting unit, an associated contact subassembly,and an electronics unit. In some embodiments, the contacts 28 aremounted on or in a subassembly hereinafter referred to as a contactsubassembly 26 (see FIG. 5A), which includes a contact holder 34configured to fit within the base 24 of the mounting unit 14 and a hinge38 that allows the contact subassembly 26 to pivot between a firstposition (for insertion) and a second position (for use) relative to themounting unit 14, which is described in more detail with reference toFIGS. 11 and 12. The term “hinge” as used herein is a broad term and isused in its ordinary sense, including, without limitation, to refer toany of a variety of pivoting, articulating, and/or hinging mechanisms,such as an adhesive hinge, a sliding joint, and the like; the term hingedoes not necessarily imply a fulcrum or fixed point about which thearticulation occurs.

In certain embodiments, the mounting unit 14 is provided with anadhesive pad 8, preferably disposed on the mounting unit's back surfaceand preferably including a releasable backing layer 9. Thus, removingthe backing layer 9 and pressing the base portion 24 of the mountingunit onto the host's skin adheres the mounting unit 14 to the host'sskin. Additionally or alternatively, an adhesive pad can be placed oversome or all of the sensor system after sensor insertion is complete toensure adhesion, and optionally to ensure an airtight seal or watertightseal around the wound exit-site (or sensor insertion site) (not shown).Appropriate adhesive pads can be chosen and designed to stretch,elongate, conform to, and/or aerate the region (e.g., host's skin).

In preferred embodiments, the adhesive pad 8 is formed from spun-laced,open- or closed-cell foam, and/or non-woven fibers, and includes anadhesive disposed thereon, however a variety of adhesive padsappropriate for adhesion to the host's skin can be used, as isappreciated by one skilled in the art of medical adhesive pads. In someembodiments, a double-sided adhesive pad is used to adhere the mountingunit to the host's skin. In other embodiments, the adhesive pad includesa foam layer, for example, a layer wherein the foam is disposed betweenthe adhesive pad's side edges and acts as a shock absorber.

In some embodiments, the surface area of the adhesive pad 8 is greaterthan the surface area of the mounting unit's back surface.Alternatively, the adhesive pad can be sized with substantially the samesurface area as the back surface of the base portion. Preferably, theadhesive pad has a surface area on the side to be mounted on the host'sskin that is greater than about 1, 1.25, 1.5, 1.75, 2, 2.25, or 2.5times the surface area of the back surface 25 of the mounting unit base24. Such a greater surface area can increase adhesion between themounting unit and the host's skin, minimize movement between themounting unit and the host's skin, and/or protect the wound exit-site(sensor insertion site) from environmental and/or biologicalcontamination. In some alternative embodiments, however, the adhesivepad can be smaller in surface area than the back surface assuming asufficient adhesion can be accomplished.

In some embodiments, the adhesive pad 8 is substantially the same shapeas the back surface 25 of the base 24, although other shapes can also beadvantageously employed, for example, butterfly-shaped, round, square,or rectangular. The adhesive pad backing can be designed for two-steprelease, for example, a primary release wherein only a portion of theadhesive pad is initially exposed to allow adjustable positioning of thedevice, and a secondary release wherein the remaining adhesive pad islater exposed to firmly and securely adhere the device to the host'sskin once appropriately positioned. The adhesive pad is preferablywaterproof. Preferably, a stretch-release adhesive pad is provided onthe back surface of the base portion to enable easy release from thehost's skin at the end of the useable life of the sensor, as isdescribed in more detail with reference to FIGS. 10A to 10C.

In some circumstances, it has been found that a conventional bondbetween the adhesive pad and the mounting unit may not be sufficient,for example, due to humidity that can cause release of the adhesive padfrom the mounting unit. Accordingly, in some embodiments, the adhesivepad can be bonded using a bonding agent activated by or accelerated byan ultraviolet, acoustic, radio frequency, or humidity cure. In someembodiments, a eutectic bond of first and second composite materials canform a strong adhesion. In some embodiments, the surface of the mountingunit can be pretreated utilizing ozone, plasma, chemicals, or the like,in order to enhance the bondability of the surface.

A bioactive agent is preferably applied locally at the insertion site(exit-site) prior to or during sensor insertion. Suitable bioactiveagents include those which are known to discourage or prevent bacterialgrowth and infection, for example, anti-inflammatory agents,antimicrobials, antibiotics, or the like. It is believed that thediffusion or presence of a bioactive agent can aid in prevention orelimination of bacteria adjacent to the exit-site. Additionally oralternatively, the bioactive agent can be integral with or coated on theadhesive pad, or no bioactive agent at all is employed.

FIG. 5A is an exploded perspective view of the contact subassembly 26 inone embodiment, showing its individual components. Preferably, awatertight (waterproof or water-resistant) sealing member 36, alsoreferred to as a sealing material or seal, fits within a contact holder34 and provides a watertight seal configured to surround the electricalconnection at the electrode terminals within the mounting unit in orderto protect the electrodes (and the respective operable connection withthe contacts of the electronics unit 16) from damage due to moisture,humidity, dirt, and other external environmental factors. In oneembodiment, the sealing member 36 is formed from an elastomericmaterial, such as silicone; however, a variety of other elastomeric orsealing materials can also be used, for example, silicone-polyurethanehybrids, polyurethanes, and polysulfides. Preferably, the sealing memberis configured to compress within the contact subassembly when theelectronics unit is mated to the mounting unit. In some embodiments, thesealing member 36 comprises a self-lubricating material, for example,self-lubricating silicone or other materials impregnated with orotherwise comprising a lubricant configured to be released during use.In some embodiments, the sealing member 36 includes a self-sealingmaterial, for example, one that leaches out a sealant such as a siliconeoil. In some embodiments, bumps, ridges, or other raised portions (notshown), can be added to a component of the sensor system, such as to thecontact subassembly 26 (e.g., housing adjacent to the sealing member),electronics unit 16 and/or sealing member 36 to provide additionalcompression and improve the seal formed around the contacts 28 and/orsensor 32 when the contacts 28 are mated to the sensor electronics.

Preferably, the sealing member is selected using a durometer. Adurometer is an instrument used for measuring the indentation hardnessof rubber, plastics, and other materials. Durometers are built tovarious standards from ASTM, DIN, JIS, and ISO. The hardness of plasticsis most commonly measured by the Shore (Durometer) test or Rockwellhardness test. Both methods measure the resistance of plastics towardindentation and provide an empirical hardness value. Shore Hardness,using either the Shore A or Shore D scale, is the preferred method forrubbers/elastomers and is also commonly used for softer plastics such aspolyolefins, fluoropolymers, and vinyls. The Shore A scale is used forsofter rubbers while the Shore D scale is used for harder ones. Inpreferred embodiments, the Shore A scale is employed in connection withselection of a sealing member.

The Shore hardness is measured with a Durometer and sometimes referredto as “Durometer hardness.” The hardness value is determined by thepenetration of the Durometer indenter foot into the sample. Because ofthe resilience of rubbers and plastics, the indentation reading maychange over time, so the indentation time is sometimes reported alongwith the hardness number. The ASTM test method designation for the ShoreDurometer hardness test is ASTM D2240. The results obtained from thistest are a useful measure of relative resistance to indentation ofvarious grades of polymers.

Using a durometer in the selection of a sealing member enables selectionof a material with optimal durometer hardness that balances theadvantages of a lower durometer hardness with the advantages of a higherdurometer hardness. For example, when a guide tube (e.g., cannula) isutilized to maintain an opening in a silicone sealing member prior tosensor insertion, a compression set (e.g., some retention of acompressed shape caused by compression of the material over time) withinthe silicone can result due to compression over time of the sealingmember by the guide tube. Compression set can also result from certainsterilization procedures (e.g., radiation sterilization such as electronbeam or gamma radiation). Unfortunately, in some circumstances, thecompression set of the sealing member may cause gaps or incompletenessof contact between the sealing member and the contacts and/or sensor. Ingeneral, a lower durometer hardness provides a better conformation(e.g., seal) surrounding the contacts and/or sensor as compared to ahigher durometer hardness. Additionally, a lower durometer hardnessenables a design wherein less force is required to create the seal(e.g., to snap the electronics unit into the mounting unit, for example,as in the embodiment illustrated in FIG. 5A) as compared to a higherdurometer hardness, thereby increasing the ease of use of the device.However, the benefits of a lower durometer hardness silicone materialmust be balanced with potential disadvantages in manufacturing. Forexample, lower durometer hardness silicones are often produced bycompounding with a silicone oil. In some circumstances, it is believedthat some silicone oil may leach or migrate during manufacture and/orsterilization, which may corrupt aspects of the manufacturing process(e.g., adhesion of glues and/or effectiveness of coating processes).Additionally, a higher durometer hardness material generally providesgreater stability of the material, which may reduce or avoid damage tothe sealing member cause by pressure or other forces.

It is generally preferred that a sealing member 36 with a durometerhardness of from about 5 to about 80 Shore A is employed, morepreferably a durometer hardness of from about 10 to about 50 Shore A,and even more preferably from about 20 to about 50 Shore A. In oneembodiment, of a transcutaneous analyte sensor, the sealing member isfabricated using a silicone of about 20 Shore A to maximize theconformance of the seal around the contacts and/or sensor whileminimizing the force required to compress the silicone for thatconformance. In another embodiment, the sealing member is formed from asilicone of about 50 Shore A so as to provide increased strength of thesealing member (e.g., its resistance to compression). While a fewrepresentative examples have been provided above, one skilled in the artappreciates that higher or lower durometer hardness sealing material mayalso be suitable for use.

In one alternative embodiment, a sealing member 36 with a durometerhardness of about 10 Shore A is used. In this embodiment, the sealingmaterial tends to “weep” out, further increasing conformance of the sealagainst the adjacent parts. In another alternative embodiment, a sealingmaterial with a durometer hardness of about 0 (zero) Shore A is used asa sealant and/or in combination with a sealant, also referred to as alubricant, which in some embodiments is a hydrophobic fluid fillingmaterial such as a grease, silicone, petroleum jelly, or the like.Preferably, the sensor and/or contacts are encased in a housing thatcontains the sealant, causing the material to “squeeze” around contactsand/or sensor. Any suitable hydrophobic fluid filling material can beemployed. Especially preferred are synthetic or petroleumhydrocarbon-based materials, silicone-based materials, ester-basedgreases, and other pharmaceutical-grade materials.

In some embodiments, the sealing member can comprise a material that hasbeen modified to enhance the desirable properties of the sealing member36. For example, one or more filler materials or stiffening agents suchas glass beads, polymer beads, composite beads, beads comprising variousinert materials, carbon black, talc, titanium oxide, silicone dioxide,and the like. In some embodiments, the filler material is incorporatedinto the sealing member material to mechanically stiffen the sealingmember. In general, however, use of a filler material or stiffeningagent in the sealing member material can provide a variety of enhancedproperties including increased modulus of elasticity, crosslink density,hardness, and stiffness, and decreased creep, for example. In somealternative embodiments, gases are chemically (or otherwise) injectedinto the sealing member material. For example, the sealing material cancomprise a polymeric foam (e.g., a polyurethane foam, a latex foam, astyrene-butadiene foam, and the like), or a dispersion of gas bubbles ina grease or jelly.

In alternative embodiments, the seal 36 is designed to form aninterference fit with the electronics unit and can be formed from avariety of materials, for example, flexible plastics, or noble metals.One of ordinary skill in the art appreciates that a variety of designscan be employed to provide a seal surrounding electrical contacts suchas described herein. For example, the contact holder 34 can beintegrally designed as a part of the mounting unit, rather than as aseparate piece thereof. Additionally or alternatively, a sealant can beprovided in or around the sensor (e.g., within or on the contactsubassembly or sealing member), such as is described in more detail withreference to FIGS. 12A and 12B. In general, sealing materials withdurometer hardnesses in the described ranges can provide improvedsealing in a variety of sensor applications. For example, a sealingmember as described in the preferred embodiments (e.g., selected using adurometer to ensure optimal durometer hardness, and the like) can beimplemented adjacent to and/or to at least partially surrounding thesensor in a variety of sensor designs, including, for example, thesensor designs of the preferred embodiments, as well as a planarsubstrate such as described in U.S. Pat. No. 6,175,752.

In the illustrated embodiment of FIG. 5A, the sealing member 36 isformed with a raised portion 37 surrounding the contacts 28. The raisedportion 37 enhances the interference fit surrounding the contacts 28when the electronics unit 16 is mated to the mounting unit 14. Namely,the raised portion surrounds each contact and presses against theelectronics unit 16 to form a tight seal around the electronics unit.However, a variety of alternative sealing member configurations aredescribed with reference to FIGS. 5D to 5H, below.

Contacts 28 fit within the seal 36 and provide for electrical connectionbetween the sensor 32 and the electronics unit 16. In general, thecontacts are designed to ensure a stable mechanical and electricalconnection of the electrodes that form the sensor 32 (see FIG. 6A to 6C)to mutually engaging contacts 28 thereon. A stable connection can beprovided using a variety of known methods, for example, domed metalliccontacts, cantilevered fingers, pogo pins, or the like, as isappreciated by one skilled in the art.

In preferred embodiments, the contacts 28 are formed from a conductiveelastomeric material, such as a carbon black elastomer, through whichthe sensor 32 extends (see FIGS. 11B and 12B). Conductive elastomers areadvantageously employed because their resilient properties create anatural compression against mutually engaging contacts, forming a securepress fit therewith. In some embodiments, conductive elastomers can bemolded in such a way that pressing the elastomer against the adjacentcontact performs a wiping action on the surface of the contact, therebycreating a cleaning action during initial connection. Additionally, inpreferred embodiments, the sensor 32 extends through the contacts 28wherein the sensor is electrically and mechanically secure by therelaxation of elastomer around the sensor (see FIGS. 8A to 8D).

In an alternative embodiment, a conductive, stiff plastic forms thecontacts, which are shaped to comply upon application of pressure (forexample, a leaf-spring shape). Contacts of such a configuration can beused instead of a metallic spring, for example, and advantageously avoidthe need for crimping or soldering through compliant materials;additionally, a wiping action can be incorporated into the design toremove contaminants from the surfaces during connection. Non-metalliccontacts can be advantageous because of their seamlessmanufacturability, robustness to thermal compression, non-corrosivesurfaces, and native resistance to electrostatic discharge (ESD) damagedue to their higher-than-metal resistance.

FIGS. 5B and 5C are perspective views of alternative contactconfigurations. FIG. 5B is an illustration of a narrow contactconfiguration. FIG. 5C is an illustration of a wide contactconfiguration. One skilled in the art appreciates that a variety ofconfigurations are suitable for the contacts of the preferredembodiments, whether elastomeric, stiff plastic or other materials areused. In some circumstances, it can be advantageous to provide multiplecontact configurations (such as illustrated in FIGS. 5A to 5C) todifferentiate sensors from each other. In other words, the architectureof the contacts can include one or more configurations each designed(keyed) to fit with a particular electronics unit.

FIGS. 5D to 5H are schematic cross-sectional views of a portion of thecontact subassembly; namely, a variety of alternative embodiments of thesealing member 36 are illustrated. In each of these embodiments (e.g.,FIGS. 5D to 5H), a sensor 32 is shown, which is configured for operableconnection to sensor electronics for measuring an analyte in a host suchas described in more detail elsewhere herein. Additionally, twoelectrical contacts 28, as described in more detail elsewhere herein,are configured to operably connect the sensor to the sensor electronics.Thus, the sealing member 36 in each of these alternative configurations(e.g., FIGS. 5D to 5H) at least partially surrounds the sensor and/orthe electrical contacts to seal the electrical contacts from moisturewhen the sensor is operably connected to the sensor electronics.

FIG. 5D is a schematic cross-sectional view of the sealing member 36 inan embodiment similar to FIG. 5A, including gaps 400 that are maintainedwhen the one or more electrical contacts are operably connected to thesensor electronics. Preferably, these air gaps provide for someflexibility of the sealing member 36 to deform or compress to seal theelectrical contacts 28 from moisture or other environmental effects.

In certain circumstances, such as during sensor insertion orneedle/guide tube retraction (see FIGS. 8A to 8D), a sealing member witha certain elasticity can be compressed or deformed by the insertionand/or retraction forces applied thereto. Accordingly in someembodiments, the sealing member is configured to be maintained (e.g.,held substantially in place) on the housing (e.g., contact subassembly26 or base 34) without substantial translation, deformation, and/orcompression (e.g., during sensor insertion). FIG. 5D illustrates onesuch implementation, wherein one or more depressions 402 are configuredto receive mating protrusions (e.g., on the base 34 of the contactsubassembly 26, not shown). A variety of male-female or other suchmechanical structures can be implemented to hold the sealing member inplace, as is appreciated by one skilled in the art. In one alternativeembodiment, an adhesive (not shown) is configured to adhere the sealingmember 36 to the housing (e.g., base 34 of the contact subassembly 26)to provide substantially the same benefit of holding the sealing memberduring sensor insertion/retraction without substantial deformation, asdescribed in more detail, above. In another embodiment, the base 34 ofthe contact subassembly 26 (or equivalent structure) comprisesreinforcing mechanical supports configured to hold the sealing member asdescribed above. One skilled in the art appreciates a variety ofmechanical and/or chemical methods that can be implemented to maintain asealing member substantially stationary (e.g., without substantialtranslation, deformation and/or compression) when compression and/ordeformation forces are applied thereto. Although one exemplaryembodiment is illustrated with reference to FIG. 5D, a wide variety ofsystems and methods for holding the sealing member can be implementedwith a sealing member of any particular design.

FIG. 5E is a schematic cross-sectional view of the sealing member 36 inan alternative embodiment without gaps. In certain circumstances, fullcontact between mating members may be preferred.

In certain circumstances moisture may “wick” along the length of thesensor (e.g., from an exposed end) through the sealing member 36 to thecontacts 28. FIG. 5F is a schematic cross-sectional view of a sealingmember 36 in an alternative embodiment wherein one or more gaps 400 areprovided. In this embodiment, the gaps 400 extend into the sealingmember and encompass at least a portion of the sensor 32. The gaps 400or “deep wells” of FIG. 5F are designed to interrupt the path thatmoisture may take, avoiding contact of the moisture at the contacts 28.If moisture is able to travel along the path of the sensor, the abruptchange of surface tension at the opening 404 of the gap 400 in thesealing member 36 substantially deters the moisture from traveling tothe contacts 28.

FIG. 5G is a schematic cross-sectional view of the sealing member 36 inanother alternative embodiment wherein one or more gaps 400 areprovided. In this embodiment, the gaps extend from the bottom side ofthe sealing member 36, which can be helpful in maintaining a stableposition of the contacts 28 and/or reduces “pumping” of air gaps in somesituations.

In some embodiments, gaps 400 can be filled by a sealant, which also maybe referred to as a lubricant, for example, oil, grease, or gel. In oneexemplary embodiment, the sealant includes petroleum jelly and is usedto provide a moisture barrier surrounding the sensor. Referring to FIG.5F, filling the gaps 400 with a sealant provides an additional moisturebarrier to reduce or avoid moisture from traveling to the contacts 28.Sealant can be used to fill gaps or crevices in any sealing memberconfiguration.

In some sealing member configurations, it can be advantageous to providea channel 406 through the sealing member 36 in order to create anadditional pathway for sealant (e.g. lubricant) in order to expel airand/or to provide a path for excess sealant to escape. In someembodiments, more than one channel is provided.

FIG. 5H is a schematic cross-sectional view of a sealing member 36 in analternative embodiment wherein a large gap 400 is provided between thesealing member upper portion 408 and the sealing member lower portion410. These portions 408, 410 may or may not be connected; however, theyare configured to sandwich the sensor and sealant (e.g., grease)therebetween. The sealing member 36 illustrated with reference to FIG.5H can provide ease of manufacture and/or product assembly with acomprehensive sealing ability. Additional gaps (with or without sealant)can be provided in a variety of locations throughout the sealing member36; these additional gaps, for example, provide space for excesssealant.

Sensor

Preferably, the sensor 32 includes a distal portion 42, also referred toas the in vivo portion, adapted to extend out of the mounting unit forinsertion under the host's skin, and a proximal portion 40, alsoreferred to as an ex vivo portion, adapted to remain above the host'sskin after sensor insertion and to operably connect to the electronicsunit 16 via contacts 28. Preferably, the sensor 32 includes two or moreelectrodes: a working electrode 44 and at least one additionalelectrode, which can function as a counter electrode and/or referenceelectrode, hereinafter referred to as the reference electrode 46. Amembrane system is preferably deposited over the electrodes, such asdescribed in more detail with reference to FIGS. 6A to 6C, below.

FIG. 6A is an expanded cutaway view of a proximal portion 40 of thesensor in one embodiment, showing working and reference electrodes. Inthe illustrated embodiments, the working and reference electrodes 44, 46extend through the contacts 28 to form electrical connection therewith(see FIGS. 11B and 12B). Namely, the working electrode 44 is inelectrical contact with one of the contacts 28 and the referenceelectrode 46 is in electrical contact with the other contact 28, whichin turn provides for electrical connection with the electronics unit 16when it is mated with the mounting unit 14. Mutually engaging electricalcontacts permit operable connection of the sensor 32 to the electronicsunit 16 when connected to the mounting unit 14; however other methods ofelectrically connecting the electronics unit 16 to the sensor 32 arealso possible. In some alternative embodiments, for example, thereference electrode can be configured to extend from the sensor andconnect to a contact at another location on the mounting unit (e.g.,non-coaxially). Detachable connection between the mounting unit 14 andelectronics unit 16 provides improved manufacturability, namely, therelatively inexpensive mounting unit 14 can be disposed of whenreplacing the sensor system after its usable life, while the relativelymore expensive electronics unit 16 can be reused with multiple sensorsystems.

In alternative embodiments, the contacts 28 are formed into a variety ofalternative shapes and/or sizes. For example, the contacts 28 can bediscs, spheres, cuboids, and the like. Furthermore, the contacts 28 canbe designed to extend from the mounting unit in a manner that causes aninterference fit within a mating cavity or groove of the electronicsunit, forming a stable mechanical and electrical connection therewith.

FIG. 6B is an expanded cutaway view of a distal portion of the sensor inone embodiment, showing working and reference electrodes. In preferredembodiments, the sensor is formed from a working electrode 44 and areference electrode 46 helically wound around the working electrode 44.An insulator 45 is disposed between the working and reference electrodesto provide necessary electrical insulation therebetween. Certainportions of the electrodes are exposed to enable electrochemicalreaction thereon, for example, a window 43 can be formed in theinsulator to expose a portion of the working electrode 44 forelectrochemical reaction.

In preferred embodiments, each electrode is formed from a fine wire witha diameter of from about 0.001 or less to about 0.010 inches or more,for example, and is formed from, e.g., a plated insulator, a platedwire, or bulk electrically conductive material. Although the illustratedelectrode configuration and associated text describe one preferredmethod of forming a transcutaneous sensor, a variety of knowntranscutaneous sensor configurations can be employed with thetranscutaneous analyte sensor system of the preferred embodiments, suchas U.S. Pat. No. 5,711,861 to Ward et al., U.S. Pat. No. 6,642,015 toVachon et al., U.S. Pat. No. 6,654,625 to Say et al., U.S. Pat. No.6,565,509 to Say et al., U.S. Pat. No. 6,514,718 to Heller, U.S. Pat.No. 6,465,066 to Essenpreis et al., U.S. Pat. No. 6,214,185 toOffenbacher et al., U.S. Pat. No. 5,310,469 to Cunningham et al., andU.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No. 6,579,690 toBonnecaze et al., U.S. Pat. No. 6,484,046 to Say et al., U.S. Pat. No.6,512,939 to Colvin et al., U.S. Pat. No. 6,424,847 to Mastrototaro etal., U.S. Pat. No. 6,424,847 to Mastrototaro et al., for example. All ofthe above patents are not inclusive of all applicable analyte sensors;in general, it should be understood that the disclosed embodiments areapplicable to a variety of analyte sensor configurations. Much of thedescription of the preferred embodiments, for example the membranesystem described below, can be implemented not only with in vivosensors, but also with in vitro sensors, such as blood glucose meters(SMBG).

In preferred embodiments, the working electrode comprises a wire formedfrom a conductive material, such as platinum, platinum-iridium,palladium, graphite, gold, carbon, conductive polymer, alloys, or thelike. Although the electrodes can by formed by a variety ofmanufacturing techniques (bulk metal processing, deposition of metalonto a substrate, or the like), it can be advantageous to form theelectrodes from plated wire (e.g., platinum on steel wire) or bulk metal(e.g., platinum wire). It is believed that electrodes formed from bulkmetal wire provide superior performance (e.g., in contrast to depositedelectrodes), including increased stability of assay, simplifiedmanufacturability, resistance to contamination (e.g., which can beintroduced in deposition processes), and improved surface reaction(e.g., due to purity of material) without peeling or delamination.

The working electrode 44 is configured to measure the concentration ofan analyte. In an enzymatic electrochemical sensor for detectingglucose, for example, the working electrode measures the hydrogenperoxide produced by an enzyme catalyzed reaction of the analyte beingdetected and creates a measurable electronic current For example, in thedetection of glucose wherein glucose oxidase produces hydrogen peroxideas a byproduct, hydrogen peroxide reacts with the surface of the workingelectrode producing two protons (2H⁺), two electrons (2e⁻) and onemolecule of oxygen (O₂), which produces the electronic current beingdetected.

In preferred embodiments, the working electrode 44 is covered with aninsulating material 45, for example, a non-conductive polymer.Dip-coating, spray-coating, vapor-deposition, or other coating ordeposition techniques can be used to deposit the insulating material onthe working electrode. In one embodiment, the insulating materialcomprises parylene, which can be an advantageous polymer coating for itsstrength, lubricity, and electrical insulation properties. Generally,parylene is produced by vapor deposition and polymerization ofpara-xylylene (or its substituted derivatives). While not wishing to bebound by theory, it is believed that the lubricious (e.g., smooth)coating (e.g., parylene) on the sensors of the preferred embodimentscontributes to minimal trauma and extended sensor life. While parylenecoatings are generally preferred, any suitable insulating material canbe used, for example, fluorinated polymers, polyethyleneterephthalate,polyurethane, polyimide, other nonconducting polymers, or the like.Glass or ceramic materials can also be employed. Other materialssuitable for use include surface energy modified coating systems such asare marketed under the trade names AMC18, AMC148, AMC141, and AMC321 byAdvanced Materials Components Express of Bellafonte, Pa. In somealternative embodiments, however, the working electrode may not requirea coating of insulator.

The reference electrode 46, which can function as a reference electrodealone, or as a dual reference and counter electrode, is formed fromsilver, silver/silver chloride, or the like. Preferably, the referenceelectrode 46 is juxtapositioned and/or twisted with or around theworking electrode 44; however other configurations are also possible(e.g., an intradermal or on-skin reference electrode). In theillustrated embodiments, the reference electrode 46 is helically woundaround the working electrode 44. The assembly of wires is thenoptionally coated or adhered together with an insulating material,similar to that described above, so as to provide an insulatingattachment.

In some embodiments, a silver wire is formed onto the sensor asdescribed above, and subsequently chloridized to form silver/silverchloride reference electrode. Advantageously, chloridizing the silverwire as described herein enables the manufacture of a referenceelectrode with optimal in vivo performance. Namely, by controlling thequantity and amount of chloridization of the silver to formsilver/silver chloride, improved break-in time, stability of thereference electrode, and extended life has been shown with the preferredembodiments. Additionally, use of silver chloride as described aboveallows for relatively inexpensive and simple manufacture of thereference electrode.

In embodiments wherein an outer insulator is disposed, a portion of thecoated assembly structure can be stripped or otherwise removed, forexample, by hand, excimer lasing, chemical etching, laser ablation,grit-blasting (e.g., with sodium bicarbonate or other suitable grit), orthe like, to expose the electroactive surfaces. Alternatively, a portionof the electrode can be masked prior to depositing the insulator inorder to maintain an exposed electroactive surface area. In oneexemplary embodiment, grit blasting is implemented to expose theelectroactive surfaces, preferably utilizing a grit material that issufficiently hard to ablate the polymer material, while beingsufficiently soft so as to minimize or avoid damage to the underlyingmetal electrode (e.g., a platinum electrode). Although a variety of“grit” materials can be used (e.g., sand, talc, walnut shell, groundplastic, sea salt, and the like), in some preferred embodiments, sodiumbicarbonate is an advantageous grit-material because it is sufficientlyhard to ablate, e.g., a parylene coating without damaging, e.g., anunderlying platinum conductor. One additional advantage of sodiumbicarbonate blasting includes its polishing action on the metal as itstrips the polymer layer, thereby eliminating a cleaning step that mightotherwise be necessary.

In the embodiment illustrated in FIG. 6B, a radial window 43 is formedthrough the insulating material 45 to expose a circumferentialelectroactive surface of the working electrode. Additionally, sections41 of electroactive surface of the reference electrode are exposed. Forexample, the 41 sections of electroactive surface can be masked duringdeposition of an outer insulating layer or etched after deposition of anouter insulating layer.

In some applications, cellular attack or migration of cells to thesensor can cause reduced sensitivity and/or function of the device,particularly after the first day of implantation. However, when theexposed electroactive surface is distributed circumferentially about thesensor (e.g., as in a radial window), the available surface area forreaction can be sufficiently distributed so as to minimize the effect oflocal cellular invasion of the sensor on the sensor signal.Alternatively, a tangential exposed electroactive window can be formed,for example, by stripping only one side of the coated assemblystructure. In other alternative embodiments, the window can be providedat the tip of the coated assembly structure such that the electroactivesurfaces are exposed at the tip of the sensor. Other methods andconfigurations for exposing electroactive surfaces can also be employed.

In some embodiments, the working electrode has a diameter of from about0.001 inches or less to about 0.010 inches or more, preferably fromabout 0.002 inches to about 0.008 inches, and more preferably from about0.004 inches to about 0.005 inches. The length of the window can be fromabout 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078inches) or more, and preferably from about 0.5 mm (about 0.02 inches) toabout 0.75 mm (0.03 inches). In such embodiments, the exposed surfacearea of the working electrode is preferably from about 0.000013 in²(0.0000839 cm²) or less to about 0.0025 in² (0.016129 cm²) or more(assuming a diameter of from about 0.001 inches to about 0.010 inchesand a length of from about 0.004 inches to about 0.078 inches). Thepreferred exposed surface area of the working electrode is selected toproduce an analyte signal with a current in the picoAmp range, such asis described in more detail elsewhere herein. However, a current in thepicoAmp range can be dependent upon a variety of factors, for examplethe electronic circuitry design (e.g., sample rate, current draw, A/Dconverter bit resolution, etc.), the membrane system (e.g., permeabilityof the analyte through the membrane system), and the exposed surfacearea of the working electrode. Accordingly, the exposed electroactiveworking electrode surface area can be selected to have a value greaterthan or less than the above-described ranges taking into considerationalterations in the membrane system and/or electronic circuitry. Inpreferred embodiments of a glucose sensor, it can be advantageous tominimize the surface area of the working electrode while maximizing thediffusivity of glucose in order to optimize the signal-to-noise ratiowhile maintaining sensor performance in both high and low glucoseconcentration ranges.

In some alternative embodiments, the exposed surface area of the working(and/or other) electrode can be increased by altering the cross-sectionof the electrode itself. For example, in some embodiments thecross-section of the working electrode can be defined by a cross, star,cloverleaf, ribbed, dimpled, ridged, irregular, or other non-circularconfiguration; thus, for any predetermined length of electrode, aspecific increased surface area can be achieved (as compared to the areaachieved by a circular cross-section). Increasing the surface area ofthe working electrode can be advantageous in providing an increasedsignal responsive to the analyte concentration, which in turn can behelpful in improving the signal-to-noise ratio, for example.

In some alternative embodiments, additional electrodes can be includedwithin the assembly, for example, a three-electrode system (working,reference, and counter electrodes) and/or an additional workingelectrode (e.g., an electrode which can be used to generate oxygen,which is configured as a baseline subtracting electrode, or which isconfigured for measuring additional analytes). U.S. Publication No.US-2005-0161346-A1 and U.S. Publication No. US-2005-0143635-A1 describesome systems and methods for implementing and using additional working,counter, and/or reference electrodes. In one implementation wherein thesensor comprises two working electrodes, the two working electrodes arejuxtapositioned (e.g., extend parallel to each other), around which thereference electrode is disposed (e.g., helically wound). In someembodiments wherein two or more working electrodes are provided, theworking electrodes can be formed in a double-, triple-, quad-, etc.helix configuration along the length of the sensor (for example,surrounding a reference electrode, insulated rod, or other supportstructure). The resulting electrode system can be configured with anappropriate membrane system, wherein the first working electrode isconfigured to measure a first signal comprising glucose and baseline andthe additional working electrode is configured to measure a baselinesignal consisting of baseline only (e.g., configured to be substantiallysimilar to the first working electrode without an enzyme disposedthereon). In this way, the baseline signal can be subtracted from thefirst signal to produce a glucose-only signal that is substantially notsubject to fluctuations in the baseline and/or interfering species onthe signal.

Although the preferred embodiments illustrate one electrodeconfiguration including one bulk metal wire helically wound aroundanother bulk metal wire, other electrode configurations are alsocontemplated. In an alternative embodiment, the working electrodecomprises a tube with a reference electrode disposed or coiled inside,including an insulator therebetween. Alternatively, the referenceelectrode comprises a tube with a working electrode disposed or coiledinside, including an insulator therebetween. In another alternativeembodiment, a polymer (e.g., insulating) rod is provided, wherein theelectrodes are deposited (e.g., electro-plated) thereon. In yet anotheralternative embodiment, a metallic (e.g., steel) rod is provided, coatedwith an insulating material, onto which the working and referenceelectrodes are deposited. In yet another alternative embodiment, one ormore working electrodes are helically wound around a referenceelectrode.

Preferably, the electrodes and membrane systems of the preferredembodiments are coaxially formed, namely, the electrodes and/or membranesystem all share the same central axis. While not wishing to be bound bytheory, it is believed that a coaxial design of the sensor enables asymmetrical design without a preferred bend radius. Namely, in contrastto prior art sensors comprising a substantially planar configurationthat can suffer from regular bending about the plane of the sensor, thecoaxial design of the preferred embodiments do not have a preferred bendradius and therefore are not subject to regular bending about aparticular plane (which can cause fatigue failures and the like).However, non-coaxial sensors can be implemented with the sensor systemof the preferred embodiments.

In addition to the above-described advantages, the coaxial sensor designof the preferred embodiments enables the diameter of the connecting endof the sensor (proximal portion) to be substantially the same as that ofthe sensing end (distal portion) such that the needle is able to insertthe sensor into the host and subsequently slide back over the sensor andrelease the sensor from the needle, without slots or other complexmulti-component designs.

In one such alternative embodiment, the two wires of the sensor are heldapart and configured for insertion into the host in proximal butseparate locations. The separation of the working and referenceelectrodes in such an embodiment can provide additional electrochemicalstability with simplified manufacture and electrical connectivity. It isappreciated by one skilled in the art that a variety of electrodeconfigurations can be implemented with the preferred embodiments.

In some embodiments, the sensor includes an antimicrobial portionconfigured to extend through the exit-site when the sensor is implantedin the host. Namely, the sensor is designed with in vivo and ex vivoportions as described in more detail elsewhere herein; additionally, thesensor comprises a transition portion, also referred to as anantimicrobial portion, located between the in vivo and ex vivo portions42, 40. The antimicrobial portion is designed to provide antimicrobialeffects to the exit-site and adjacent tissue when implanted in the host.

In some embodiments, the antimicrobial portion comprises silver, e.g.,the portion of a silver reference electrode that is configured to extendthrough the exit-site when implanted. Although exit-site infections area common adverse occurrence associated with some conventionaltranscutaneous medical devices, the devices of preferred embodiments aredesigned at least in part to minimize infection, to minimize irritation,and/or to extend the duration of implantation of the sensor by utilizinga silver reference electrode to extend through the exit-site whenimplanted in a patient. While not wishing to be bound by theory, it isbelieved that the silver may reduce local tissue infections (within thetissue and at the exit-site); namely, steady release of molecularquantities of silver is believed to have an antimicrobial effect inbiological tissue (e.g., reducing or preventing irritation andinfection), also referred to as passive antimicrobial effects. Althoughone example of passive antimicrobial effects is described herein, oneskilled in the art can appreciate a variety of passive anti-microbialsystems and methods that can be implemented with the preferredembodiments. Additionally, it is believed that antimicrobial effects cancontribute to extended life of a transcutaneous analyte sensor, enablinga functional lifetime past a few days, e.g., seven days or longer.

In some embodiments, active antimicrobial systems and methods areprovided in the sensor system in order to further enhance theantimicrobial effects at the exit-site. In one such embodiment, anauxiliary silver wire is disposed on or around the sensor, wherein theauxiliary silver wire is connected to electronics and configured to passa current sufficient to enhance its antimicrobial properties (activeantimicrobial effects), as is appreciated by one skilled in the art. Thecurrent can be passed continuously or intermittently, such thatsufficient antimicrobial properties are provided. Although one exampleof active antimicrobial effects is described herein, one skilled in theart can appreciate a variety of active anti-microbial systems andmethods that can be implemented with the preferred embodiments.

Anchoring Mechanism

It is preferred that the sensor remains substantially stationary withinthe tissue of the host, such that migration or motion of the sensor withrespect to the surrounding tissue is minimized. Migration or motion isbelieved to cause inflammation at the sensor implant site due toirritation, and can also cause noise on the sensor signal due tomotion-related artifact, for example. Therefore, it can be advantageousto provide an anchoring mechanism that provides support for the sensor'sin vivo portion to avoid the above-mentioned problems. Combiningadvantageous sensor geometry with an advantageous anchoring minimizesadditional parts and allows for an optimally small or low profile designof the sensor. In one embodiment the sensor includes a surfacetopography, such as the helical surface topography provided by thereference electrode surrounding the working electrode. In alternativeembodiments, a surface topography could be provided by a roughenedsurface, porous surface (e.g. porous parylene), ridged surface, or thelike. Additionally (or alternatively), the anchoring can be provided byprongs, spines, barbs, wings, hooks, a bulbous portion (for example, atthe distal end), an S-bend along the sensor, a rough surface topography,a gradually changing diameter, combinations thereof, or the like, whichcan be used alone or in combination with the helical surface topographyto stabilize the sensor within the subcutaneous tissue.

Variable Stiffness

As described above, conventional transcutaneous devices are believed tosuffer from motion artifact associated with host movement when the hostis using the device. For example, when a transcutaneous analyte sensoris inserted into the host, various movements on the sensor (for example,relative movement within and between the subcutaneous space, dermis,skin, and external portions of the sensor) create stresses on thedevice, which is known to produce artifacts on the sensor signal.Accordingly, there are different design considerations (for example,stress considerations) on various sections of the sensor. For example,the distal portion 42 of the sensor can benefit in general from greaterflexibility as it encounters greater mechanical stresses caused bymovement of the tissue within the patient and relative movement betweenthe in vivo and ex vivo portions of the sensor. On the other hand, theproximal portion 40 of the sensor can benefit in general from a stiffer,more robust design to ensure structural integrity and/or reliableelectrical connections. Additionally, in some embodiments wherein aneedle is retracted over the proximal portion 40 of the device (seeFIGS. 7 to 9), a stiffer design can minimize crimping of the sensorand/or ease in retraction of the needle from the sensor. Thus, bydesigning greater flexibility into the in vivo (distal) portion 42, theflexibility is believed to compensate for patient movement, and noiseassociated therewith. By designing greater stiffness into the ex vivo(proximal) portion 40, column strength (for retraction of the needleover the sensor), electrical connections, and integrity can be enhanced.In some alternative embodiments, a stiffer distal end and/or a moreflexible proximal end can be advantageous as described in U.S.Publication No. US-2006-0015024-A1.

The preferred embodiments provide a distal portion 42 of the sensor 32designed to be more flexible than a proximal portion 40 of the sensor.The variable stiffness of the preferred embodiments can be provided byvariable pitch of any one or more helically wound wires of the device,variable cross-section of any one or more wires of the device, and/orvariable hardening and/or softening of any one or more wires of thedevice, such as is described in more detail with reference to U.S.Publication No. US-2006-0015024-A1.

Membrane System

FIG. 6C is a cross-sectional view through the sensor on line C-C of FIG.6B showing the exposed electroactive surface of the working electrodesurrounded by the membrane system in one embodiment. Preferably, amembrane system is deposited over at least a portion of theelectroactive surfaces of the sensor 32 (working electrode andoptionally reference electrode) and provides protection of the exposedelectrode surface from the biological environment, diffusion resistance(limitation) of the analyte if needed, a catalyst for enabling anenzymatic reaction, limitation or blocking of interferents, and/orhydrophilicity at the electrochemically reactive surfaces of the sensorinterface. Some examples of suitable membrane systems are described inU.S. Publication No. US-2005-0245799-A1.

In general, the membrane system includes a plurality of domains, forexample, an electrode domain 47, an interference domain 48, an enzymedomain 49 (for example, including glucose oxidase), and a resistancedomain 50, as shown in FIG. 6C, and can include a high oxygen solubilitydomain, and/or a bioprotective domain (not shown), such as is describedin more detail in U.S. Publication No. US-2005-0245799-A1. The membranesystem can be deposited on the exposed electroactive surfaces usingknown thin film techniques (for example, vapor deposition, spraying,electro-depositing, dipping, or the like). In alternative embodiments,however, other vapor deposition processes (e.g., physical and/orchemical vapor deposition processes) can be useful for providing one ormore of the insulating and/or membrane layers, including ultrasonicvapor deposition, electrostatic deposition, evaporative deposition,deposition by sputtering, pulsed laser deposition, high velocity oxygenfuel deposition, thermal evaporator deposition, electron beam evaporatordeposition, deposition by reactive sputtering molecular beam epitaxy,atmospheric pressure chemical vapor deposition (CVD), atomic layer CVD,hot wire CVD, low-pressure CVD, microwave plasma-assisted CVD,plasma-enhanced CVD, rapid thermal CVD, remote plasma-enhanced CVD, andultra-high vacuum CVD, for example. However, the membrane system can bedisposed over (or deposited on) the electroactive surfaces using anyknown method, as will be appreciated by one skilled in the art.

In some embodiments, one or more domains of the membrane systems areformed from materials such as described above in connection with theporous layer, such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones andblock copolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers. U.S. Publication No.US-2005-0245799-A1 describes biointerface and membrane systemconfigurations and materials that can be applied to the preferredembodiments.

Electrode Domain

In selected embodiments, the membrane system comprises an electrodedomain. The electrode domain 47 is provided to ensure that anelectrochemical reaction occurs between the electroactive surfaces ofthe working electrode and the reference electrode, and thus theelectrode domain 47 is preferably situated more proximal to theelectroactive surfaces than the interference and/or enzyme domain.Preferably, the electrode domain includes a coating that maintains alayer of water at the electrochemically reactive surfaces of the sensor.In other words, the electrode domain is present to provide anenvironment between the surfaces of the working electrode and thereference electrode which facilitates an electrochemical reactionbetween the electrodes. For example, a humectant in a binder materialcan be employed as an electrode domain; this allows for the fulltransport of ions in the aqueous environment. The electrode domain canalso assist in stabilizing the operation of the sensor by acceleratingelectrode start-up and drifting problems caused by inadequateelectrolyte. The material that forms the electrode domain can alsoprovide an environment that protects against pH-mediated damage that canresult from the formation of a large pH gradient due to theelectrochemical activity of the electrodes.

In one embodiment, the electrode domain 47 includes a flexible,water-swellable, hydrogel film having a “dry film” thickness of fromabout 0.05 micron or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. “Dryfilm” thickness refers to the thickness of a cured film cast from acoating formulation by standard coating techniques.

In certain embodiments, the electrode domain 47 is formed of a curablemixture of a urethane polymer and a hydrophilic polymer. Particularlypreferred coatings are formed of a polyurethane polymer havingcarboxylate or hydroxyl functional groups and non-ionic hydrophilicpolyether segments, wherein the polyurethane polymer is crosslinked witha water soluble carbodiimide (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

In some preferred embodiments, the electrode domain 47 is formed from ahydrophilic polymer such as polyvinylpyrrolidone (PVP). An electrodedomain formed from PVP has been shown to reduce break-in time of analytesensors; for example, a glucose sensor utilizing a cellulosic-basedinterference domain such as described in more detail below.

Preferably, the electrode domain is deposited by vapor deposition, spraycoating, dip coating, or other thin film techniques on the electroactivesurfaces of the sensor. In one preferred embodiment, the electrodedomain is formed by dip-coating the electroactive surfaces in anelectrode layer solution and curing the domain for a time of from about15 minutes to about 30 minutes at a temperature of from about 40° C. toabout 55° C. (and can be accomplished under vacuum (e.g., 20 to 30mmHg)). In embodiments wherein dip-coating is used to deposit theelectrode domain, a preferred insertion rate of from about 1 to about 3inches per minute into the electrode layer solution, with a preferreddwell time of from about 0.5 to about 2 minutes in the electrode layersolution, and a preferred withdrawal rate of from about 0.25 to about 2inches per minute from the electrode layer solution provide a functionalcoating. However, values outside of those set forth above can beacceptable or even desirable in certain embodiments, for example,depending upon solution viscosity and solution surface tension, as isappreciated by one skilled in the art. In one embodiment, theelectroactive surfaces of the electrode system are dip-coated one time(one layer) and cured at 50° C. under vacuum for 20 minutes.

Although an independent electrode domain 47 is described herein, in someembodiments sufficient hydrophilicity can be provided in theinterference domain and/or enzyme domain (the domain adjacent to theelectroactive surfaces) so as to provide for the full transport of ionsin the aqueous environment (e.g. without a distinct electrode domain).In these embodiments, an electrode domain is not necessary.

Interference Domain

Interferents are molecules or other species that are reduced or oxidizedat the electrochemically reactive surfaces of the sensor, eitherdirectly or via an electron transfer agent, to produce a false positiveanalyte signal. In preferred embodiments, an interference domain 48 isprovided that substantially restricts, resists, or blocks the flow ofone or more interfering species. Some known interfering species for aglucose sensor, as described in more detail above, includeacetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine,dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate,tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid. Ingeneral, the interference domain of the preferred embodiments is lesspermeable to one or more of the interfering species than to the analyte,e.g., glucose.

In one embodiment, the interference domain 48 is formed from one or morecellulosic derivatives. In general, cellulosic derivatives includepolymers such as cellulose acetate, cellulose acetate butyrate,2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetatepropionate, cellulose acetate trimellitate, and the like.

In one preferred embodiment, the interference domain 48 is formed fromcellulose acetate butyrate. Cellulose acetate butyrate with a molecularweight of from about 10,000 daltons to about 75,000 daltons, preferablyfrom about 15,000, 20,000, or 25,000 daltons to about 50,000, 55,000,60,000, 65,000, or 70,000 daltons, and more preferably about 20,000daltons is employed. In certain embodiments, however, higher or lowermolecular weights can be preferred. Additionally, a casting solution ordispersion of cellulose acetate butyrate at a weight percent of fromabout 15% to about 25%, preferably from about 15%, 16%, 17%, 18%, 19% toabout 20%, 21%, 22%, 23%, 24% or 25%, and more preferably about 18% ispreferred. Preferably, the casting solution includes a solvent orsolvent system, for example an acetone:ethanol solvent system. Higher orlower concentrations can be preferred in certain embodiments. Aplurality of layers of cellulose acetate butyrate can be advantageouslycombined to form the interference domain in some embodiments, forexample, three layers can be employed. It can be desirable to employ amixture of cellulose acetate butyrate components with differentmolecular weights in a single solution, or to deposit multiple layers ofcellulose acetate butyrate from different solutions comprising celluloseacetate butyrate of different molecular weights, differentconcentrations, and/or different chemistries (e.g., functional groups).It can also be desirable to include additional substances in the castingsolutions or dispersions, e.g., functionalizing agents, crosslinkingagents, other polymeric substances, substances capable of modifying thehydrophilicity/hydrophobicity of the resulting layer, and the like.

In one alternative embodiment, the interference domain 48 is formed fromcellulose acetate. Cellulose acetate with a molecular weight of fromabout 30,000 daltons or less to about 100,000 daltons or more,preferably from about 35,000, 40,000, or 45,000 daltons to about 55,000,60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, or 95,000daltons, and more preferably about 50,000 daltons is preferred.Additionally, a casting solution or dispersion of cellulose acetate at aweight percent of about 3% to about 10%, preferably from about 3.5%,4.0%, 4.5%, 5.0%, 5.5%, 6.0%, or 6.5% to about 7.5%, 8.0%, 8.5%, 9.0%,or 9.5%, and more preferably about 8% is preferred. In certainembodiments, however, higher or lower molecular weights and/or celluloseacetate weight percentages can be preferred. It can be desirable toemploy a mixture of cellulose acetates with molecular weights in asingle solution, or to deposit multiple layers of cellulose acetate fromdifferent solutions comprising cellulose acetates of different molecularweights, different concentrations, or different chemistries (e.g.,functional groups). It can also be desirable to include additionalsubstances in the casting solutions or dispersions such as described inmore detail above.

Layer(s) prepared from combinations of cellulose acetate and celluloseacetate butyrate, or combinations of layer(s) of cellulose acetate andlayer(s) of cellulose acetate butyrate can also be employed to form theinterference domain 48.

In some alternative embodiments, additional polymers, such as Nafion®,can be used in combination with cellulosic derivatives to provideequivalent and/or enhanced function of the interference domain 48. Asone example, a 5 wt % Nafion® casting solution or dispersion can be usedin combination with a 8 wt % cellulose acetate casting solution ordispersion, e.g., by dip coating at least one layer of cellulose acetateand subsequently dip coating at least one layer Nafion® onto aneedle-type sensor such as described with reference to the preferredembodiments. Any number of coatings or layers formed in any order may besuitable for forming the interference domain of the preferredembodiments.

In some alternative embodiments, more than one cellulosic derivative canbe used to form the interference domain 48 of the preferred embodiments.In general, the formation of the interference domain on a surfaceutilizes a solvent or solvent system in order to solvate the cellulosicderivative (or other polymer) prior to film formation thereon. Inpreferred embodiments, acetone and ethanol are used as solvents forcellulose acetate; however one skilled in the art appreciates thenumerous solvents that are suitable for use with cellulosic derivatives(and other polymers). Additionally, one skilled in the art appreciatesthat the preferred relative amounts of solvent can be dependent upon thecellulosic derivative (or other polymer) used, its molecular weight, itsmethod of deposition, its desired thickness, and the like. However, apercent solute of from about 1% to about 25% is preferably used to formthe interference domain solution so as to yield an interference domainhaving the desired properties. The cellulosic derivative (or otherpolymer) used, its molecular weight, method of deposition, and desiredthickness can be adjusted, depending upon one or more other of theparameters, and can be varied accordingly as is appreciated by oneskilled in the art.

In some alternative embodiments, other polymer types that can beutilized as a base material for the interference domain 48 includingpolyurethanes, polymers having pendant ionic groups, and polymers havingcontrolled pore size, for example. In one such alternative embodiment,the interference domain includes a thin, hydrophobic membrane that isnon-swellable and restricts diffusion of low molecular weight species.The interference domain 48 is permeable to relatively low molecularweight substances, such as hydrogen peroxide, but restricts the passageof higher molecular weight substances, including glucose and ascorbicacid. Other systems and methods for reducing or eliminating interferencespecies that can be applied to the membrane system of the preferredembodiments are described in U.S. Publication No. US-2005-0115832-A1,U.S. Publication No. US-2005-0176136-A1, U.S. Publication No.US-2005-0161346-A1, and U.S. Publication No. US-2005-0143635-A1. In somealternative embodiments, a distinct interference domain is not included.

In preferred embodiments, the interference domain 48 is depositeddirectly onto the electroactive surfaces of the sensor for a domainthickness of from about 0.05 microns or less to about 20 microns ormore, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35,0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and morepreferably still from about 1, 1.5 or 2 microns to about 2.5 or 3microns. Thicker membranes can also be desirable in certain embodiments,but thinner membranes are generally preferred because they have a lowerimpact on the rate of diffusion of hydrogen peroxide from the enzymemembrane to the electrodes.

In general, the membrane systems of the preferred embodiments can beformed and/or deposited on the exposed electroactive surfaces (e.g., oneor more of the working and reference electrodes) using known thin filmtechniques (for example, casting, spray coating, drawing down,electro-depositing, dip coating, and the like), however casting or otherknown application techniques can also be utilized. Preferably, theinterference domain is deposited by vapor deposition, spray coating, ordip coating. In one exemplary embodiment of a needle-type(transcutaneous) sensor such as described herein, the interferencedomain is formed by dip coating the sensor into an interference domainsolution using an insertion rate of from about 20 inches/min to about 60inches/min, preferably 40 inches/min, a dwell time of from about 0minute to about 5 seconds, preferably 0 seconds, and a withdrawal rateof from about 20 inches/minute to about 60 inches/minute, preferablyabout 40 inches/minute, and curing (drying) the domain from about 1minute to about 30 minutes, preferably from about 3 minutes to about 15minutes (and can be accomplished at room temperature or under vacuum(e.g., 20 to 30 mmHg)). In one exemplary embodiment including celluloseacetate butyrate interference domain, a 3-minute cure (i.e., dry) timeis preferred between each layer applied. In another exemplary embodimentemploying a cellulose acetate interference domain, a 15 minute cure(i.e., dry) time is preferred between each layer applied.

The dip process can be repeated at least one time and up to 10 times ormore. The preferred number of repeated dip processes depends upon thecellulosic derivative(s) used, their concentration, conditions duringdeposition (e.g., dipping) and the desired thickness (e.g., sufficientthickness to provide functional blocking of (or resistance to) certaininterferents), and the like. In some embodiments, 1 to 3 microns may bepreferred for the interference domain thickness; however, values outsideof these can be acceptable or even desirable in certain embodiments, forexample, depending upon viscosity and surface tension, as is appreciatedby one skilled in the art. In one exemplary embodiment, an interferencedomain is formed from three layers of cellulose acetate butyrate. Inanother exemplary embodiment, an interference domain is formed from 10layers of cellulose acetate. In alternative embodiments, theinterference domain can be formed using any known method and combinationof cellulose acetate and cellulose acetate butyrate, as will beappreciated by one skilled in the art.

In some embodiments, the electroactive surface can be cleaned prior toapplication of the interference domain 48. In some embodiments, theinterference domain 48 of the preferred embodiments can be useful as abioprotective or biocompatible domain, namely, a domain that interfaceswith host tissue when implanted in an animal (e.g., a human) due to itsstability and biocompatibility.

Enzyme Domain

In preferred embodiments, the membrane system further includes an enzymedomain 49 disposed more distally from the electroactive surfaces thanthe interference domain 48; however other configurations can bedesirable. In the preferred embodiments, the enzyme domain provides anenzyme to catalyze the reaction of the analyte and its co-reactant, asdescribed in more detail below. In the preferred embodiments of aglucose sensor, the enzyme domain includes glucose oxidase; howeverother oxidases, for example, galactose oxidase or uricase oxidase, canalso be used.

For an enzyme-based electrochemical glucose sensor to perform well, thesensor's response is preferably limited by neither enzyme activity norco-reactant concentration. Because enzymes, including glucose oxidase,are subject to deactivation as a function of time even in ambientconditions, this behavior is compensated for in forming the enzymedomain. Preferably, the enzyme domain is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, in alternative embodiments the enzyme domain is constructedfrom an oxygen enhancing material, for example, silicone, orfluorocarbon, in order to provide a supply of excess oxygen duringtransient ischemia. Preferably, the enzyme is immobilized within thedomain. See, e.g., U.S. Publication No. US-2005-0054909-A1.

In preferred embodiments, the enzyme domain is deposited onto theinterference domain for a domain thickness of from about 0.05 micron orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. However in some embodiments,the enzyme domain can be deposited directly onto the electroactivesurfaces. Preferably, the enzyme domain is deposited by spray or dipcoating. In one embodiment of needle-type (transcutaneous) sensor suchas described herein, the enzyme domain is formed by dip coating theinterference domain coated sensor into an enzyme domain solution andcuring the domain for from about 15 to about 30 minutes at a temperatureof from about 40° C. to about 55° C. (and can be accomplished undervacuum (e.g., 20 to 30 mmHg)). In embodiments wherein dip coating isused to deposit the enzyme domain at room temperature, a preferredinsertion rate of from about 0.25 inch per minute to about 3 inches perminute, with a preferred dwell time of from about 0.5 minutes to about 2minutes, and a preferred withdrawal rate of from about 0.25 inch perminute to about 2 inches per minute provides a functional coating.However, values outside of those set forth above can be acceptable oreven desirable in certain embodiments, for example, depending uponviscosity and surface tension, as is appreciated by one skilled in theart. In one embodiment, the enzyme domain is formed by dip coating twotimes (namely, forming two layers) in an enzyme domain solution andcuring at 50° C. under vacuum for 20 minutes. However, in someembodiments, the enzyme domain can be formed by dip coating and/or spraycoating one or more layers at a predetermined concentration of thecoating solution, insertion rate, dwell time, withdrawal rate, and/ordesired thickness.

Resistance Domain

In preferred embodiments, the membrane system includes a resistancedomain 50 disposed more distal from the electroactive surfaces than theenzyme domain. Although the following description is directed to aresistance domain for a glucose sensor, the resistance domain can bemodified for other analytes and co-reactants as well.

There exists a molar excess of glucose relative to the amount of oxygenin blood; that is, for every free oxygen molecule in extracellularfluid, there are typically more than 100 glucose molecules present (seeUpdike et al., Diabetes Care 5:207-21(1982)). However, an immobilizedenzyme-based glucose sensor employing oxygen as co-reactant ispreferably supplied with oxygen in non-rate-limiting excess in order forthe sensor to respond linearly to changes in glucose concentration,while not responding to changes in oxygen concentration. Specifically,when a glucose-monitoring reaction is oxygen limited, linearity is notachieved above minimal concentrations of glucose. Without asemipermeable membrane situated over the enzyme domain to control theflux of glucose and oxygen, a linear response to glucose levels can beobtained only for glucose concentrations of up to about 40 mg/dL.However, in a clinical setting, a linear response to glucose levels isdesirable up to at least about 400 mg/dL.

The resistance domain includes a semipermeable membrane that controlsthe flux of oxygen and glucose to the underlying enzyme domain,preferably rendering oxygen in a non-rate-limiting excess. As a result,the upper limit of linearity of glucose measurement is extended to amuch higher value than that which is achieved without the resistancedomain. In one embodiment, the resistance domain exhibits an oxygen toglucose permeability ratio of from about 50:1 or less to about 400:1 ormore, preferably about 200:1. As a result, one-dimensional reactantdiffusion is adequate to provide excess oxygen at all reasonable glucoseand oxygen concentrations found in the subcutaneous matrix (see Rhodeset al., Anal. Chem., 66:1520-1529 (1994)).

In alternative embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubilitydomain (for example, a silicone or fluorocarbon-based material ordomain) to enhance the supply/transport of oxygen to the enzyme domain.If more oxygen is supplied to the enzyme, then more glucose can also besupplied to the enzyme without creating an oxygen rate-limiting excess.In alternative embodiments, the resistance domain is formed from asilicone composition, such as is described in U.S. Publication No.US-2005-0090607-A1.

In a preferred embodiment, the resistance domain includes a polyurethanemembrane with both hydrophilic and hydrophobic regions to control thediffusion of glucose and oxygen to an analyte sensor, the membrane beingfabricated easily and reproducibly from commercially availablematerials. A suitable hydrophobic polymer component is a polyurethane,or polyetherurethaneurea. Polyurethane is a polymer produced by thecondensation reaction of a diisocyanate and a difunctionalhydroxyl-containing material. A polyurethaneurea is a polymer producedby the condensation reaction of a diisocyanate and a difunctionalamine-containing material. Preferred diisocyanates include aliphaticdiisocyanates containing from about 4 to about 8 methylene units.Diisocyanates containing cycloaliphatic moieties can also be useful inthe preparation of the polymer and copolymer components of the membranesof preferred embodiments. The material that forms the basis of thehydrophobic matrix of the resistance domain can be any of those known inthe art as appropriate for use as membranes in sensor devices and ashaving sufficient permeability to allow relevant compounds to passthrough it, for example, to allow an oxygen molecule to pass through themembrane from the sample under examination in order to reach the activeenzyme or electrochemical electrodes. Examples of materials which can beused to make non-polyurethane type membranes include vinyl polymers,polyethers, polyesters, polyamides, inorganic polymers such aspolysiloxanes and polycarbosiloxanes, natural polymers such ascellulosic and protein based materials, and mixtures or combinationsthereof.

In a preferred embodiment, the hydrophilic polymer component ispolyethylene oxide. For example, one useful hydrophobic-hydrophiliccopolymer component is a polyurethane polymer that includes about 20%hydrophilic polyethylene oxide. The polyethylene oxide portions of thecopolymer are thermodynamically driven to separate from the hydrophobicportions of the copolymer and the hydrophobic polymer component. The 20%polyethylene oxide-based soft segment portion of the copolymer used toform the final blend affects the water pick-up and subsequent glucosepermeability of the membrane.

In preferred embodiments, the resistance domain is deposited onto theenzyme domain to yield a domain thickness of from about 0.05 microns orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. Preferably, the resistancedomain is deposited onto the enzyme domain by vapor deposition, spraycoating, or dip coating. In one preferred embodiment, spray coating isthe preferred deposition technique. The spraying process atomizes andmists the solution, and therefore most or all of the solvent isevaporated prior to the coating material settling on the underlyingdomain, thereby minimizing contact of the solvent with the enzyme.

In another preferred embodiment, physical vapor deposition (e.g.,ultrasonic vapor deposition) is used for coating one or more of themembrane domain(s) onto the electrodes, wherein the vapor depositionapparatus and process include an ultrasonic nozzle that produces a mistof micro-droplets in a vacuum chamber. In these embodiments, themicro-droplets move turbulently within the vacuum chamber, isotropicallyimpacting and adhering to the surface of the substrate. Advantageously,vapor deposition as described above can be implemented to provide highproduction throughput of membrane deposition processes (e.g., at leastabout 20 to about 200 or more electrodes per chamber), greaterconsistency of the membrane on each sensor, and increased uniformity ofsensor performance, for example, as described below.

In some embodiments, depositing the resistance domain (for example, asdescribed in the preferred embodiments above) includes formation of amembrane system that substantially blocks or resists ascorbate (a knownelectrochemical interferant in hydrogen peroxide-measuring glucosesensors). While not wishing to be bound by theory, it is believed thatduring the process of depositing the resistance domain as described inthe preferred embodiments, a structural morphology is formed that ischaracterized in that ascorbate does not substantially permeatetherethrough.

In a preferred embodiment, the resistance domain is deposited on theenzyme domain by spray coating a solution of from about 1 wt. % to about5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent. Inspraying a solution of resistance domain material, including a solvent,onto the enzyme domain, it is desirable to mitigate or substantiallyreduce any contact with enzyme of any solvent in the spray solution thatcan deactivate the underlying enzyme of the enzyme domain.Tetrahydrofuran (THF) is one solvent that minimally or negligiblyaffects the enzyme of the enzyme domain upon spraying. Other solventscan also be suitable for use, as is appreciated by one skilled in theart.

Although a variety of spraying or deposition techniques can be used,spraying the resistance domain material and rotating the sensor at leastone time by 180° can typically provide adequate coverage by theresistance domain. Spraying the resistance domain material and rotatingthe sensor at least two times by 120° provides even greater coverage(one layer of 360° coverage), thereby ensuring resistivity to glucose,such as is described in more detail above.

In preferred embodiments, the resistance domain is spray coated andsubsequently cured for a time of from about 15 minutes to about 90minutes at a temperature of from about 40° C. to about 60° C. (and canbe accomplished under vacuum (e.g., from 20 to 30 mmHg)). A cure time ofup to about 90 minutes or more can be advantageous to ensure completedrying of the resistance domain.

In one embodiment, the resistance domain is formed by spray coating atleast six layers (namely, rotating the sensor seventeen times by 120°for at least six layers of 360° coverage) and curing at 50° C. undervacuum for 60 minutes. However, the resistance domain can be formed bydip coating or spray coating any layer or plurality of layers, dependingupon the concentration of the solution, insertion rate, dwell time,withdrawal rate, and/or the desired thickness of the resulting film.Additionally, curing in a convention oven can also be employed.

In certain embodiments, a variable frequency microwave oven can be usedto cure the membrane domains/layers. In general, microwave ovensdirectly excite the rotational mode of solvents. Consequently, microwaveovens cure coatings from the inside out rather than from the outside inas with conventional convection ovens. This direct rotational modeexcitation is responsible for the typically observed “fast” curingwithin a microwave oven. In contrast to conventional microwave ovens,which rely upon a fixed frequency of emission that can cause arcing ofdielectric (metallic) substrates if placed within a conventionalmicrowave oven, Variable Frequency Microwave (VFM) ovens emit thousandsof frequencies within 100 milliseconds, which substantially eliminatesarcing of dielectric substrates. Consequently, the membranedomains/layers can be cured even after deposition on metallic electrodesas described herein. While not wishing to be bound by theory, it isbelieve that VFM curing can increase the rate and completeness ofsolvent evaporation from a liquid membrane solution applied to a sensor,as compared to the rate and completeness of solvent evaporation observedfor curing in conventional convection ovens.

In certain embodiments, VFM is can be used together with convection ovencuring to further accelerate cure time. In some sensor applicationswherein the membrane is cured prior to application on the electrode(see, for example, U.S. Publication No. US-2005-0245799-A1),conventional microwave ovens (e.g., fixed frequency microwave ovens) canbe used to cure the membrane layer.

Treatment of Interference Domain/Membrane System

Although the above-described methods generally include a curing step information of the membrane system, including the interference domain, thepreferred embodiments further include an additional treatment step,which can be performed directly after the formation of the interferencedomain and/or some time after the formation of the entire membranesystem (or anytime in between). In some embodiments, the additionaltreatment step is performed during (or in combination with)sterilization of the sensor.

In some embodiments, the membrane system (or interference domain) istreated by exposure to ionizing radiation, for example, electron beamradiation, UV radiation, X-ray radiation, gamma radiation, and the like.Alternatively, the membrane can be exposed to visible light whensuitable photoinitiators are incorporated into the interference domain.While not wishing to be bound by theory, it is believed that exposingthe interference domain to ionizing radiation substantially crosslinksthe interference domain and thereby creates a tighter, less permeablenetwork than an interference domain that has not been exposed toionizing radiation.

In some embodiments, the membrane system (or interference domain) iscrosslinked by forming free radicals, which may include the use ofionizing radiation, thermal initiators, chemical initiators,photoinitiators (e.g., UV and visible light), and the like. Any suitableinitiator or any suitable initiator system can be employed, for example,α-hydroxyketone, α-aminoketone, ammonium persulfate (APS), redox systemssuch as APS/bisulfite, or potassium permanganate. Suitable thermalinitiators include but are not limited to potassium persulfate, ammoniumpersulfate, sodium persulfate, and mixtures thereof

In embodiments wherein electron beam radiation is used to treat themembrane system (or interference domain), a preferred exposure time isfrom about 6 k or 12 kGy to about 25 or 50 kGy, more preferably about 25kGy. However, one skilled in the art appreciates that choice ofmolecular weight, composition of cellulosic derivative (or otherpolymer), and/or the thickness of the layer can affect the preferredexposure time of membrane to radiation. Preferably, the exposure issufficient for substantially crosslinking the interference domain toform free radicals, but does not destroy or significantly break down themembrane or does not significantly damage the underlying electroactivesurfaces.

In embodiments wherein UV radiation is employed to treat the membrane,UV rays from about 200 nm to about 400 nm are preferred; however valuesoutside of this range can be employed in certain embodiments, dependentupon the cellulosic derivative and/or other polymer used.

In some embodiments, for example, wherein photoinitiators are employedto crosslink the interference domain, one or more additional domains canbe provided adjacent to the interference domain for preventingdelamination that may be caused by the crosslinking treatment. Theseadditional domains can be “tie layers” (i.e., film layers that enhanceadhesion of the interference domain to other domains of the membranesystem). In one exemplary embodiment, a membrane system is formed thatincludes the following domains: resistance domain, enzyme domain,electrode domain, and cellulosic-based interference domain, wherein theelectrode domain is configured to ensure adhesion between the enzymedomain and the interference domain. In embodiments whereinphotoinitiators are employed to crosslink the interference domain, UVradiation of greater than about 290 nm is preferred. Additionally, fromabout 0.01 to about 1 wt % photoinitiator is preferred weight-to-weightwith a preselected cellulosic polymer (e.g., cellulose acetate); howevervalues outside of this range can be desirable dependent upon thecellulosic polymer selected.

In general, sterilization of the transcutaneous sensor can be completedafter final assembly, utilizing methods such as electron beam radiation,gamma radiation, glutaraldehyde treatment, or the like. The sensor canbe sterilized prior to or after packaging. In an alternative embodiment,one or more sensors can be sterilized using variable frequency microwavechamber(s), which can increase the speed and reduce the cost of thesterilization process. In another alternative embodiment, one or moresensors can be sterilized using ethylene oxide (EtO) gas sterilization,for example, by treating with 100% ethylene oxide, which can be usedwhen the sensor electronics are not detachably connected to the sensorand/or when the sensor electronics must undergo a sterilization process.In one embodiment, one or more packaged sets of transcutaneous sensors(e.g., 1, 2, 3, 4, or 5 sensors or more) are sterilized simultaneously.

Mutarotase Enzyme

In some embodiments, mutarotase, an enzyme that converts α D-glucose toβ D-glucose, is incorporated into the membrane system. Mutarotase can beincorporated into the enzyme domain and/or can be incorporated intoanother domain of the membrane system. In general, glucose exists in twodistinct isomers, α and β, which are in equilibrium with one another insolution and in the blood or interstitial fluid. At equilibrium, α ispresent at a relative concentration of about 35.5% and β is present inthe relative concentration of about 64.5% (see Okuda et. al., AnalBiochem. 1971 September; 43(1):312-5). Glucose oxidase, which is aconventional enzyme used to react with glucose in glucose sensors,reacts with β D-glucose and not with α D-glucose. Since only the βD-glucose isomer reacts with the glucose oxidase, errant readings mayoccur in a glucose sensor responsive to a shift of the equilibriumbetween the α D-glucose and the β D-glucose. Many compounds, such ascalcium, can affect equilibrium shifts of α D-glucose and β D-glucose.For example, as disclosed in U.S. Pat. No. 3,964,974 to Banaugh et al.,compounds that exert a mutarotation accelerating effect on α D-glucoseinclude histidine, aspartic acid, imidazole, glutamic acid, α hydroxylpyridine, and phosphate.

Accordingly, a shift in α D-glucose and β D-glucose equilibrium cancause a glucose sensor based on glucose oxidase to err high or low. Toovercome the risks associated with errantly high or low sensor readingsdue to equilibrium shifts, the sensor of the preferred embodiments canbe configured to measure total glucose in the host, including αD-glucose and β D-glucose by the incorporation of the mutarotase enzyme,which converts α D-glucose to β D-glucose.

Although sensors of some embodiments described herein include aninterference domain in order to block or reduce one or moreinterferents, sensors with the membrane systems of the preferredembodiments, including an electrode domain 47, an enzyme domain 48, anda resistance domain 49, have been shown to inhibit ascorbate without anadditional interference domain. Namely, the membrane system of thepreferred embodiments, including an electrode domain 47, an enzymedomain 48, and a resistance domain 49, has been shown to besubstantially non-responsive to ascorbate in physiologically acceptableranges. While not wishing to be bound by theory, it is believed that theprocessing process of spraying the depositing the resistance domain byspray coating, as described herein, forms results in a structuralmorphology that is substantially resistance resistant to ascorbate.

Oxygen Conduit

As described above, certain sensors depend upon an enzyme within themembrane system through which the host's bodily fluid passes and inwhich the analyte (for example, glucose) within the bodily fluid reactsin the presence of a co-reactant (for example, oxygen) to generate aproduct. The product is then measured using electrochemical methods, andthus the output of an electrode system functions as a measure of theanalyte. For example, when the sensor is a glucose oxidase based glucosesensor, the species measured at the working electrode is H₂O₂. Anenzyme, glucose oxidase, catalyzes the conversion of oxygen and glucoseto hydrogen peroxide and gluconate according to the following reaction:

Glucose+O₂→Gluconate+H₂O₂

Because for each glucose molecule reacted there is a proportional changein the product, H₂O₂, one can monitor the change in H₂O₂ to determineglucose concentration. Oxidation of H₂O₂ by the working electrode isbalanced by reduction of ambient oxygen, enzyme generated H₂O₂ and otherreducible species at a counter electrode, for example. See Fraser, D.M., “An Introduction to In vivo Biosensing: Progress and Problems.” In“Biosensors and the Body,” D. M. Fraser, ed., 1997, pp. 1-56 John Wileyand Sons, New York)).

In vivo, glucose concentration is generally about one hundred times ormore that of the oxygen concentration. Consequently, oxygen is alimiting reactant in the electrochemical reaction, and when insufficientoxygen is provided to the sensor, the sensor is unable to accuratelymeasure glucose concentration. Thus, depressed sensor function orinaccuracy is believed to be a result of problems in availability ofoxygen to the enzyme and/or electroactive surface(s).

Accordingly, in an alternative embodiment, an oxygen conduit (forexample, a high oxygen solubility domain formed from silicone orfluorochemicals) is provided that extends from the ex vivo portion ofthe sensor to the in vivo portion of the sensor to increase oxygenavailability to the enzyme. The oxygen conduit can be formed as a partof the coating (insulating) material or can be a separate conduitassociated with the assembly of wires that forms the sensor.

Porous Biointerface Materials

In alternative embodiments, the distal portion 42 includes a porousmaterial disposed over some portion thereof, which modifies the host'stissue response to the sensor. In some embodiments, the porous materialsurrounding the sensor advantageously enhances and extends sensorperformance and lifetime in the short term by slowing or reducingcellular migration to the sensor and associated degradation that wouldotherwise be caused by cellular invasion if the sensor were directlyexposed to the in vivo environment. Alternatively, the porous materialcan provide stabilization of the sensor via tissue ingrowth into theporous material in the long term. Suitable porous materials includesilicone, polytetrafluoroethylene, expanded polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinylalcohol (PVA), polybutylene terephthalate (PBT), polymethylmethacrylate(PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes,cellulosic polymers, polysulfones and block copolymers thereofincluding, for example, di-block, tri-block, alternating, random andgraft copolymers, as well as metals, ceramics, cellulose, hydrogelpolymers, poly (2-hydroxyethyl methacrylate, pHEMA), hydroxyethylmethacrylate, (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC),high density polyethylene, acrylic copolymers, nylon, polyvinyldifluoride, polyanhydrides, poly(1-lysine), poly (L-lactic acid),hydroxyethylmethacrylate, hydroxyapeptite, alumina, zirconia, carbonfiber, aluminum, calcium phosphate, titanium, titanium alloy, nintinol,stainless steel, and CoCr alloy, or the like, such as are described inU.S. Publication No. US-2005-0031689-A1 and U.S. Publication No.US-2005-0112169-A1.

In some embodiments, the porous material surrounding the sensor providesunique advantages in the short term (e.g., one to 30 days) that can beused to enhance and extend sensor performance and lifetime. However,such materials can also provide advantages in the long term too (e.g.,greater than 30 days) and thus are useful in the long term sensorsdescribed below. Particularly, the in vivo portion of the sensor (theportion of the sensor that is implanted into the host's tissue) isencased (partially or fully) in a porous material. The porous materialcan be wrapped around the sensor (for example, by wrapping the porousmaterial around the sensor or by inserting the sensor into a section ofporous material sized to receive the sensor). Alternately, the porousmaterial can be deposited on the sensor (for example, by electrospinningof a polymer directly thereon). In yet other alternative embodiments,the sensor is inserted into a selected section of porous biomaterial.Other methods for surrounding the in vivo portion of the sensor with aporous material can also be used as is appreciated by one skilled in theart.

The porous material surrounding the sensor advantageously slows orreduces cellular migration to the sensor and associated degradation thatwould otherwise be caused by cellular invasion if the sensor weredirectly exposed to the in vivo environment. Namely, the porous materialprovides a barrier that makes the migration of cells towards the sensormore tortuous and therefore slower (providing short term advantages). Itis believed that this reduces or slows the sensitivity loss normallyobserved in a short-term sensor over time.

In an embodiment wherein the porous material is a high oxygen solubilitymaterial, such as porous silicone, the high oxygen solubility porousmaterial surrounds some of or the entire in vivo portion 42 of thesensor. High oxygen solubility materials are materials that dynamicallyretain a high availability of oxygen that can be used to compensate forthe local oxygen deficit during times of transient ischemia (e.g.,silicone and fluorocarbons). It is believed that some signal noisenormally seen by a conventional sensor can be attributed to an oxygendeficit. In one exemplary embodiment, porous silicone surrounds thesensor and thereby effectively increases the concentration of oxygenlocal (proximal) to the sensor. Thus, an increase in oxygen availabilityproximal to the sensor as achieved by this embodiment ensures that anexcess of oxygen over glucose is provided to the sensor; therebyreducing the likelihood of oxygen limited reactions therein.Accordingly, by providing a high oxygen solubility material (e.g.,porous silicone) surrounding the in vivo portion of the sensor, it isbelieved that increased oxygen availability, reduced signal noise,longevity, and ultimately enhanced sensor performance can be achieved.

Bioactive Agents

In some alternative embodiments, a bioactive agent is incorporated intothe above described porous material and/or membrane system, whichdiffuses out into the environment adjacent to the sensing region, suchas is described in U.S. Publication No. US-2005-0031689-A1. Additionallyor alternately, a bioactive agent can be administered locally at theexit-site or implantation-site. Suitable bioactive agents are those thatmodify the host's tissue response to the sensor, for exampleanti-inflammatory agents, anti-infective agents, anesthetics,inflammatory agents, growth factors, immunosuppressive agents,antiplatelet agents, anti-coagulants, anti-proliferates, ACE inhibitors,cytotoxic agents, anti-barrier cell compounds, vascularization-inducingcompounds, anti-sense molecules, or mixtures thereof, such as aredescribed in more detail in co-pending U.S. Patent Publication No.US-2005-0031689-A1.

In embodiments wherein the porous material is designed to enhanceshort-term (e.g., from about 1 to about 30 days) lifetime or performanceof the sensor, a suitable bioactive agent can be chosen to ensure thattissue ingrowth does not substantially occur within the pores of theporous material. Namely, by providing a tissue modifying bioactiveagent, such as an anti-inflammatory agent (for example, Dexamethasone),substantially tissue ingrowth can be inhibited, at least in the shortterm, in order to maintain sufficient glucose transport through thepores of the porous material to maintain a stable sensitivity.

In embodiments wherein the porous material is designed to enhancelong-term (e.g., from about a day to about a year or more) lifetime orperformance of the sensor, a suitable bioactive agent, such as avascularization-inducing compound or anti-barrier cell compound, can bechosen to encourage tissue ingrowth without barrier cell formation.

In some alternative embodiments, the in vivo portion of the sensor isdesigned with porosity therethrough, for example, a design wherein thesensor wires are configured in a mesh, loose helix configuration(namely, with spaces between the wires), or with micro-fabricated holestherethrough. Porosity within the sensor modifies the host's tissueresponse to the sensor, because tissue ingrowth into and/or through thein vivo portion of the sensor increases stability of the sensor and/orimproves host acceptance of the sensor, thereby extending the lifetimeof the sensor in vivo.

Sensor Manufacture

In some embodiments, the sensor is manufactured partially or whollyusing a continuous reel-to-reel process, wherein one or moremanufacturing steps are automated. In such embodiments, a manufacturingprocess can be provided substantially without the need for manualmounting and fixing steps and substantially without the need humaninteraction. A process can be utilized wherein a plurality of sensors ofthe preferred embodiments, including the electrodes, insulator, andmembrane system, are continuously manufactured in a semi-automated orautomated process.

In one embodiment, a plurality of twisted pairs is continuously formedinto a coil, wherein a working electrode is coated with an insulatormaterial around which a plurality of reference electrodes is wound. Theplurality of twisted pairs are preferably indexed and subsequently movedfrom one station to the next whereby the membrane system is seriallydeposited according to the preferred embodiments. Preferably, the coilis continuous and remains as such during the entire sensor fabricationprocess, including winding of the electrodes, insulator application, andmembrane coating processes. After drying of the membrane system, eachindividual sensor is cut from the continuous coil.

A continuous reel-to-reel process for manufacturing the sensoreliminates possible sensor damage due to handling by eliminatinghandling steps, and provides faster manufacturing due to faster troubleshooting by isolation when a product fails. Additionally, a process runcan be facilitated because of elimination of steps that would otherwisebe required (e.g., steps in a manual manufacturing process). Finally,increased or improved product consistency due to consistent processeswithin a controlled environment can be achieved in a machine or robotdriven operation.

In certain embodiments, vapor deposition (e.g., physical vapordeposition) is utilized to deposit one or more of the membrane domainsonto the sensor. Vapor deposition can be used to coat one or moreinsulating layers onto the electrodes and one or more of the domains ofthe membrane system onto the electrochemically reactive surfaces. Thevapor deposition process can be a part of a continuous manufacturingprocess, for example, a semi-automated or fully-automated manufacturingprocess. Physical vapor deposition processes are generally preferred. Insuch physical vapor deposition processes in the gas phase for forming athin film, source material is physically transferred in a vacuum to thesubstrate without any chemical reaction(s) involved. Physical vapordeposition processes include evaporation (e.g., by thermal or e-beam)and sputtering processes. In alternative embodiments, chemical vapordeposition can be used. In chemical vapor deposition processes fordepositing a thin film, the substrate is exposed to one or more volatileprecursors, which react and/or decompose on the substrate surface toproduce the desired deposit. Advantageously, vapor deposition processescan be implemented to provide high production throughput of membranedeposition processes (e.g., deposition on at least about 20 to about 200or more electrodes per chamber), greater consistency of the membrane oneach sensor, and increased uniformity of sensor performance.

Applicator

FIG. 7 is an exploded side view of an applicator, showing the componentsthat enable sensor and needle insertion. In this embodiment, theapplicator 12 includes an applicator body 18 that aides in aligning andguiding the applicator components. Preferably, the applicator body 18includes an applicator body base 60 that matingly engages the mountingunit 14 and an applicator body cap 62 that enables appropriaterelationships (for example, stops) between the applicator components.

The guide tube subassembly 20 includes a guide tube carrier 64 and aguide tube 66. In some embodiments, the guide tube is a cannula. Theguide tube carrier 64 slides along the applicator body 18 and maintainsthe appropriate relative position of the guide tube 66 during insertionand subsequent retraction. For example, prior to and during insertion ofthe sensor, the guide tube 66 extends through the contact subassembly 26to maintain an opening that enables easy insertion of the needletherethrough (see FIGS. 8A to 8D). During retraction of the sensor, theguide tube subassembly 20 is pulled back, engaging with and causing theneedle and associated moving components to retract back into theapplicator 12 (See FIGS. 8C and 8D). In some embodiments, a lubricant(e.g., petroleum jelly) is placed within the sealing member 36 of thecontact subassembly such that it surrounds the guide tube (e.g.,cannula), thereby allowing the guide tube to easily retract back intothe applicator, for example, without causing compression or deformationof the sealing member 36.

A needle subassembly 68 is provided that includes a needle carrier 70and needle 72. The needle carrier 70 cooperates with the otherapplicator components and carries the needle 72 between its extended andretracted positions. The needle can be of any appropriate size that canencompass the sensor 32 and aid in its insertion into the host.Preferred sizes include from about 32 gauge or less to about 18 gauge ormore, more preferably from about 28 gauge to about 25 gauge, to providea comfortable insertion for the host. Referring to the inner diameter ofthe needle, approximately 0.006 inches to approximately 0.023 inches ispreferable, and 0.013 inches is most preferable. The needle carrier 70is configured to engage with the guide tube carrier 64, while the needle72 is configured to slidably nest within the guide tube 66, which allowsfor easy guided insertion (and retraction) of the needle through thecontact subassembly 26.

A push rod subassembly 74 is provided that includes a push rod carrier76 and a push rod 78. The push rod carrier 76 cooperates with otherapplicator components to ensure that the sensor is properly insertedinto the host's skin, namely the push rod carrier 76 carries the pushrod 78 between its extended and retracted positions. In this embodiment,the push rod 78 is configured to slidably nest within the needle 72,which allows for the sensor 32 to be pushed (released) from the needle72 upon retraction of the needle, which is described in more detail withreference to FIGS. 8A through 8D. In some embodiments, a slight bend orserpentine shape is designed into or allowed in the sensor in order tomaintain the sensor within the needle by interference. While not wishingto be bound by theory, it is believed that a slight friction fit of thesensor within the needle minimizes motion of the sensor duringwithdrawal of the needle and maintains the sensor within the needleprior to withdrawal of the needle.

A plunger subassembly 22 is provided that includes a plunger 80 andplunger cap 82. The plunger subassembly 22 cooperates with otherapplicators components to ensure proper insertion and subsequentretraction of the applicator components. In this embodiment, the plunger80 is configured to engage with the push rod to ensure the sensorremains extended (namely, in the host) during retraction, such as isdescribed in more detail with reference to FIG. 8C.

Sensor Insertion

FIGS. 8A through 8D are schematic side cross-sectional views thatillustrate the applicator components and their cooperating relationshipsat various stages of sensor insertion. FIG. 8A illustrates the needleand sensor loaded prior to sensor insertion. FIG. 8B illustrates theneedle and sensor after sensor insertion. FIG. 8C illustrates the sensorand needle during needle retraction. FIG. 8D illustrates the sensorremaining within the contact subassembly after needle retraction.Although the embodiments described herein suggest manual insertionand/or retraction of the various components, automation of one or moreof the stages can also be employed. For example, spring-loadedmechanisms that can be triggered to automatically insert and/or retractthe sensor, needle, or other cooperative applicator components can beimplemented.

Referring to FIG. 8A, the sensor 32 is shown disposed within the needle72, which is disposed within the guide tube 66. In this embodiment, theguide tube 66 is provided to maintain an opening within the contactsubassembly 26 and/or contacts 28 to provide minimal friction betweenthe needle 72 and the contact subassembly 26 and/or contacts 28 duringinsertion and retraction of the needle 72. However, the guide tube is anoptional component, which can be advantageous in some embodimentswherein the contact subassembly 26 and/or the contacts 28 are formedfrom an elastomer or other material with a relatively high frictioncoefficient, and which can be omitted in other embodiments wherein thecontact subassembly 26 and or the contacts 28 are formed from a materialwith a relatively low friction coefficient (for example, hard plastic ormetal). A guide tube, or the like, can be preferred in embodimentswherein the contact subassembly 26 and/or the contacts 28 are formedfrom a material designed to frictionally hold the sensor 32 (see FIG.8D), for example, by the relaxing characteristics of an elastomer, orthe like. In these embodiments, the guide tube is provided to easeinsertion of the needle through the contacts, while allowing for africtional hold of the contacts on the sensor 32 upon subsequent needleretraction. Stabilization of the sensor in or on the contacts 28 isdescribed in more detail with reference to FIG. 8D and following.Although FIG. 8A illustrates the needle and sensor inserted into thecontacts subassembly as the initial loaded configuration, alternativeembodiments contemplate a step of loading the needle through the guidetube 66 and/or contacts 28 prior to sensor insertion.

Referring to FIG. 8B, the sensor 32 and needle 72 are shown in anextended position. In this stage, the pushrod 78 has been forced to aforward position, for example by pushing on the plunger shown in FIG. 7,or the like. The plunger 22 (FIG. 7) is designed to cooperate with otherof the applicator components to ensure that sensor 32 and the needle 72extend together to a forward position (as shown); namely, the push rod78 is designed to cooperate with other of the applicator components toensure that the sensor 32 maintains the forward position simultaneouslywithin the needle 72.

Referring to FIG. 8C, the needle 72 is shown during the retractionprocess. In this stage, the push rod 78 is held in its extended(forward) position in order to maintain the sensor 32 in its extended(forward) position until the needle 72 has substantially fully retractedfrom the contacts 28. Simultaneously, the cooperating applicatorcomponents retract the needle 72 and guide tube 66 backward by a pullingmotion (manual or automated) thereon. In preferred embodiments, theguide tube carrier 64 (FIG. 7) engages with cooperating applicatorcomponents such that a backward (retraction) motion applied to the guidetube carrier retracts the needle 72 and guide tube 66, without(initially) retracting the push rod 78. In an alternative embodiment,the push rod 78 can be omitted and the sensor 32 held it its forwardposition by a cam, elastomer, or the like, which is in contact with aportion of the sensor while the needle moves over another portion of thesensor. One or more slots can be cut in the needle to maintain contactwith the sensor during needle retraction.

Referring to FIG. 8D, the needle 72, guide tube 66, and push rod 78 areall retracted from contact subassembly 26, leaving the sensor 32disposed therein. The cooperating applicator components are designedsuch that when the needle 72 has substantially cleared from the contacts28 and/or contact subassembly 26, the push rod 78 is retracted alongwith the needle 72 and guide tube 66. The applicator 12 can then bereleased (manually or automatically) from the contacts 28, such as isdescribed in more detail elsewhere herein, for example with reference toFIGS. 9D and 10A.

The preferred embodiments are generally designed with elastomericcontacts to ensure a retention force that retains the sensor 32 withinthe mounting unit 14 and to ensure stable electrical connection of thesensor 32 and its associated contacts 28. Although the illustratedembodiments and associated text describe the sensor 32 extending throughthe contacts 28 to form a friction fit therein, a variety ofalternatives are contemplated. In one alternative embodiment, the sensoris configured to be disposed adjacent to the contacts (rather thanbetween the contacts). The contacts can be constructed in a variety ofknown configurations, for example, metallic contacts, cantileveredfingers, pogo pins, or the like, which are configured to press againstthe sensor after needle retraction.

It is generally preferred that a contact 28 is formed from a materialwith a durometer hardness of from about 5 to about 80 Shore A, morepreferably from about 10 to about 50 Shore A, and even more preferablyfrom about 20 to about 50 Shore A. In one implementation of atranscutaneous analyte sensor as described with reference to thepreferred embodiments, the contact 28 is formed from a material with adurometer hardness of about 20 Shore A to maximize conformance (e.g.,compression) of the contact around the sensor and/or within the sealingmember. In another implementation of a transcutaneous analyte sensor asdescribed with reference to the preferred embodiments, the contact 28 isformed from a material with a durometer hardness of about 50 Shore A toincrease the strength of the contact 28 (e.g., increase resistance tocompression). While a few examples have been provided above, one skilledin the art will appreciate that higher or lower durometer hardnesssealing materials can also be advantageously employed.

In some embodiments, the durometer hardness of the elastomeric contacts28 is higher than the durometer hardness of the sealing member 36. Inone example, the durometer hardness of the contacts is about 50 Shore Aand the durometer hardness of the sealing member is about 20 Shore A;however, a variety of durometer hardness materials within the preferredrange (typically, from about 5 Shore A to about 80 Shore A) can bechosen. In these embodiments, the higher durometer hardness contactsgenerally provide greater stability while the lower durometer hardnesssealing member generally provides superior compression and/or sealaround the contacts.

In some embodiments, the durometer hardness of the sealing member 36 ishigher than the durometer hardness of the elastomeric contacts 28. Inone example, the durometer hardness of the sealing member is about 50Shore A and the durometer hardness of the contacts is about 20 Shore A,however a variety of durometer hardness materials within the preferredrange (typically, from about 5 Shore A to about 80 Shore A) can bechosen. In these embodiments, the higher durometer hardness sealingmember provides greater stability while the lower durometer hardnesscontacts provide superior compression and/or seal.

The illustrated embodiments are designed with coaxial contacts 28;namely, the contacts 28 are configured to contact the working andreference electrodes 44, 46 axially along the distal portion 42 of thesensor 32 (see FIG. 6A). As shown in FIG. 6A, the working electrode 44extends farther than the reference electrode 46, which allows coaxialconnection of the electrodes 44, 46 with the contacts 28 at locationsspaced along the distal portion of the sensor (see also FIGS. 10B and11B). Although the illustrated embodiments employ a coaxial design,other designs are contemplated within the scope of the preferredembodiments. For example, the reference electrode can be positionedsubstantially adjacent to (but spaced apart from) the working electrodeat the distal portion of the sensor. In this way, the contacts 28 can bedesigned side-by-side rather than co-axially along the axis of thesensor.

FIG. 9A is a perspective view of an applicator and mounting unit in oneembodiment including a safety latch mechanism 84. The safety latchmechanism 84 is configured to lock the plunger subassembly 22 in astationary position such that it cannot be accidentally pushed prior torelease of the safety latch mechanism. In this embodiment, the sensorsystem 10 is preferably packaged (e.g., shipped) in this lockedconfiguration, wherein the safety latch mechanism 84 holds the plungersubassembly 22 in its extended position, such that the sensor 32 cannotbe prematurely inserted (e.g., accidentally released). The safety latchmechanism 84 is configured such that a pulling force shown in thedirection of the arrow (see FIG. 9A) releases the lock of the safetylatch mechanism on the plunger subassembly, thereby allowing sensorinsertion. Although one safety latch mechanism that locks the plungersubassembly is illustrated and described herein, a variety of safetylatch mechanism configurations that lock the sensor to prevent it fromprematurely releasing (i.e., that lock the sensor prior to release ofthe safety latch mechanism) are contemplated, as can be appreciated byone skilled in the art, and fall within the scope of the preferredembodiments.

FIG. 9A additionally illustrates a force-locking mechanism 86 includedin certain alternative embodiments of the sensor system, wherein theforce-locking mechanism 86 is configured to ensure a proper mate betweenthe electronics unit 16 and the mounting unit 14 (see FIG. 13A, forexample). In embodiments wherein a seal is formed between the mountingunit and the electronics unit, as described in more detail elsewhereherein, an appropriate force may be required to ensure a seal hassufficiently formed therebetween; in some circumstances, it can beadvantageous to ensure the electronics unit has been properly mated(e.g., snap-fit or sealingly mated) to the mounting unit. Accordingly,upon release of the applicator 12 from the mounting unit 14 (aftersensor insertion), and after insertion of the electronics unit 16 intothe mounting unit 14, the force-locking mechanism 86 allows the user toensure a proper mate and/or seal therebetween. In practice, a userpivots (e.g., lifts or twists) the force-locking mechanism such that itprovides force on the electronics unit 16 by pulling up on the circulartab illustrated in FIG. 9A; the force-locking mechanism is preferablyreleased thereafter. Although one system and one method for providing asecure and/or sealing fit between the electronics unit and the mountingunit are illustrated, various other force-locking mechanisms can beemployed that utilize a variety of systems and methods for providing asecure and/or sealing fit between the electronics unit and the mountingunit (housing).

FIGS. 9B to 9D are side views of an applicator and mounting unit in oneembodiment, showing various stages of sensor insertion. FIG. 9B is aside view of the applicator matingly engaged to the mounting unit priorto sensor insertion. FIG. 9C is a side view of the mounting unit andapplicator after the plunger subassembly has been pushed, extending theneedle and sensor from the mounting unit (namely, through the host'sskin). FIG. 9D is a side view of the mounting unit and applicator afterthe guide tube subassembly has been retracted, retracting the needleback into the applicator. Although the drawings and associated textillustrate and describe embodiments wherein the applicator is designedfor manual insertion and/or retraction, automated insertion and/orretraction of the sensor/needle, for example, using spring-loadedcomponents, can alternatively be employed.

The preferred embodiments advantageously provide a system and method foreasy insertion of the sensor and subsequent retraction of the needle ina single push-pull motion. Because of the mechanical latching system ofthe applicator, the user provides a continuous force on the plunger cap82 and guide tube carrier 64 that inserts and retracts the needle in acontinuous motion. When a user grips the applicator, his or her fingersgrasp the guide tube carrier 64 while his or her thumb (or anotherfinger) is positioned on the plunger cap 82. The user squeezes his orher fingers and thumb together continuously, which causes the needle toinsert (as the plunger slides forward) and subsequently retract (as theguide tube carrier slides backward) due to the system of latches locatedwithin the applicator (FIGS. 7 to 9) without any necessary change ofgrip or force, leaving the sensor implanted in the host. In someembodiments, a continuous torque, when the applicator components areconfigured to rotatingly engage one another, can replace the continuousforce. Some prior art sensors, in contrast to the sensors of thepreferred embodiments, suffer from complex, multi-step, ormulti-component insertion and retraction steps to insert and remove theneedle from the sensor system.

FIG. 9B shows the mounting unit and applicator in the ready position.The sensor system can be shipped in this configuration, or the user canbe instructed to mate the applicator 12 with the mounting unit 14 priorto sensor insertion. The insertion angle a is preferably fixed by themating engagement of the applicator 12. In the illustrated embodiment,the insertion angle a is fixed in the applicator 12 by the angle of theapplicator body base 60 with the shaft of the applicator body 18.However, a variety of systems and methods of ensuring proper placementcan be implemented. Proper placement ensures that at least a portion ofthe sensor 32 extends below the dermis of the host upon insertion. Inalternative embodiments, the sensor system 10 is designed with a varietyof adjustable insertion angles. A variety of insertion angles can beadvantageous to accommodate a variety of insertion locations and/orindividual dermis configurations (for example, thickness of the dermis).In preferred embodiments, the insertion angle a is from about 0 to about90 degrees, more preferably from about 30 to about 60 degrees, and evenmore preferably about 45 degrees.

In practice, the mounting unit is placed at an appropriate location onthe host's skin, for example, the skin of the arm, thigh, or abdomen.Thus, removing the backing layer 9 from the adhesive pad 8 and pressingthe base portion of the mounting unit on the skin adheres the mountingunit to the host's skin.

FIG. 9C shows the mounting unit and applicator after the needle 72 hasbeen extended from the mounting unit 14 (namely, inserted into the host)by pushing the push rod subassembly 22 into the applicator 12. In thisposition, the sensor 32 is disposed within the needle 72 (namely, inposition within the host), and held by the cooperating applicatorcomponents. In alternative embodiments, the mounting unit and/orapplicator can be configured with the needle/sensor initially extended.In this way, the mechanical design can be simplified and theplunger-assisted insertion step can be eliminated or modified. Theneedle can be simply inserted by a manual force to puncture the host'sskin, and only one (pulling) step is required on the applicator, whichremoves the needle from the host's skin.

FIG. 9D shows the mounting unit and applicator after the needle 72 hasbeen retracted into the applicator 12, exposing the sensor 32 to thehost's tissue. During needle retraction, the push rod subassemblymaintains the sensor in its extended position (namely, within the host).In preferred embodiments, retraction of the needle irreversibly locksthe needle within the applicator so that it cannot be accidentallyand/or intentionally released, reinserted, or reused. The applicator ispreferably configured as a disposable device to reduce or eliminate apossibility of exposure of the needle after insertion into the host.However a reusable or reloadable applicator is also contemplated in somealternative embodiments. After needle retraction, the applicator 12 canbe released from the mounting unit, for example, by pressing the releaselatch(es) 30, and the applicator disposed of appropriately. Inalternative embodiments, other mating and release configurations can beimplemented between the mounting unit and the applicator, or theapplicator can automatically release from the mounting unit after sensorinsertion and subsequent needle retraction. In one alternativeembodiment, a retention hold (e.g., ball and detent configuration) holdsand releases the electronics unit (or applicator).

In one alternative embodiment, the mounting unit is configured toreleasably mate with the applicator and electronics unit in a mannersuch that when the applicator is releasably mated to the mounting unit(e.g., after sensor insertion), the electronics unit is configured toslide into the mounting unit, thereby triggering release of theapplicator and simultaneous mating of the electronics unit to themounting unit. Cooperating mechanical components, for example, slidingball and detent type configurations, can be used to accomplish thesimultaneous mating of electronics unit and release of the applicator.

FIGS. 9E to 9G are perspective views of a sensor system 310 of analternative embodiment, including an applicator 312, electronics unit316, and mounting unit 314, showing various stages of applicator releaseand/or electronic unit mating. FIG. 9E is a perspective view of theapplicator matingly engaged to the mounting unit after sensor insertion.FIG. 9F is a perspective view of the mounting unit and applicatormatingly engaged while the electronics unit is slidingly inserted intothe mounting unit. FIG. 9G is a perspective view of the electronics unitmatingly engaged with the mounting unit after the applicator has beenreleased.

In general, the sensor system 310 comprises a sensor adapted fortranscutaneous insertion into a host's skin; a housing 314 adapted forplacement adjacent to the host's skin; an electronics unit 316releasably attachable to the housing; and an applicator 312 configuredto insert the sensor through the housing 314 and into the skin of thehost, wherein the applicator 312 is adapted to releasably mate with thehousing 314, and wherein the system 310 is configured to release theapplicator 312 from the housing when the electronics unit 316 isattached to the housing 314.

FIG. 9E shows the sensor system 310 after the sensor has been insertedand prior to release of the applicator 312. In this embodiment, theelectronics unit 316 is designed to slide into the mounting unit 314.Preferably, the electronics unit 316 is configured and arranged to slideinto the mounting unit 314 in only one orientation. In the illustratedembodiment, the insertion end is slightly tapered and dovetailed inorder to guide insertion of the electronics unit 316 into the housing314; however other self-alignment configurations are possible. In thisway, the electronics unit 316 self-aligns and orients the electronicsunit 316 in the housing, ensuring a proper fit and a secure electronicconnection with the sensor.

FIG. 9F shows the sensor system 310 after the electronics unit 316 hasbeen inserted therein. Preferably, the electronic unit 316 slide-fitsinto the mounting unit. In some embodiments, the sensor system 310 canbe designed to allow the electronics unit 316 to be attached to themounting unit 314 (i.e., operably connected to the sensor) before thesensor system 310 is affixed to the host. Advantageously, this designprovides mechanical stability for the sensor during transmitterinsertion.

FIG. 9G shows the sensor system 310 upon release of the applicator 312from the mounting unit 314 and electronics unit 316. In this embodiment,the sensor system 310 is configured such that mating the electronicsunit to the mounting unit triggers the release of the applicator 312from the mounting unit 314.

Thus, the above described sensor system 310, also referred to as theslide-in system, allows for self-alignment of the electronics unit,creates an improved seal around the contacts due to greater holdingforce, provides mechanical stability for the sensor during insertion ofthe electronics unit, and causes automatic release of the applicator andsimultaneous lock of the electronics unit into the mounting unit.

Although the overall design of the sensor system 10 results in aminiaturized volume as compared to numerous conventional devices, asdescribed in more detail below; the sensor system 310 further enables areduction in volume, as compared to, for example, the sensor system 10described above.

FIGS. 9H and 9I are comparative top views of the sensor system shown inthe alternative embodiment illustrated in FIGS. 9E to 9G and compared tothe embodiments illustrated elsewhere (see FIGS. 1 to 3 and 10 to 12,for example). Namely, the alternative embodiment described withreference to FIGS. 9E to 9G further enables reduced size (e.g., mass,volume, and the like) of the device as compared to certain otherdevices. It has been discovered that the size (including volume and/orsurface area) of the device can affect the function of the device. Forexample, motion of the mounting unit/electronics unit caused by externalinfluences (e.g., bumping or other movement on the skin) is translatedto the sensor in vivo, causing motion artifact (e.g., an effect on thesignal, or the like). Accordingly, by enabling a reduction of size, amore stable signal with overall improved patient comfort can beachieved.

Accordingly, slide-in system 310 described herein, including the systemsand methods for inserting the sensor and connecting the electronics unitto the mounting unit, enables the mounting unit 316/electronics unit 314subassembly to have a volume of less than about 10 cm³, more preferablyless than about 8 cm³, and even more preferably less than about 6 cm³, 5cm³, or 4 cm³ or less. In general, the mounting unit 316/electronicsunit 314 subassembly comprises a first major surface and a second majorsurface opposite the first major surface. The first and second majorsurfaces together preferably account for at least about 50% of thesurface area of the device; the first and second major surfaces eachdefine a surface area, wherein the surface area of each major surface isless than or equal to about 10 cm², preferably less than or equal toabout 8 cm², and more preferably less than or equal to about 6.5 cm², 6cm², 5.5 cm², 5 cm², 4.5 cm², or 4 cm² or less. Typically, the mountingunit 316/electronics unit 314 subassembly has a length 320 of less thanabout 40 mm by a width 322 of less than about 20 mm and a thickness ofless than about 10 mm, and more preferably a length 320 less than orequal to about 35 mm by a width 322 less than or equal to about 18 mm bya thickness of less than or equal to about 9 mm.

In some embodiments, the mounting unit 14/electronics unit 16 assemblyhas the following dimensional properties: preferably a length of about 6cm or less, more preferably about 5 cm or less, more preferably stillabout 4.6 cm or less, even more preferably 4 cm or less, and mostpreferably about 3 cm or less; preferably a width of about 5 cm or less,more preferably about 4 cm or less, even more preferably 3 cm or less,even more preferably still about 2 cm or less, and most preferably about1.5 cm or less; and/or preferably a thickness of about 2 cm or less,more preferably about 1.3 cm or less, more preferably still about 1 cmor less, even more preferably still about 0.7 cm or less, and mostpreferably about 0.5 cm or less. The mounting unit 14/electronics unit16 assembly preferably has a volume of about 20 cm³ or less, morepreferably about 10 cm³ or less, more preferably still about 5 cm³ orless, and most preferably about 3 cm³ or less; and preferably weighs 12g or less, more preferably about 9 g or less, and most preferably about6 g or less, although in some embodiments the electronics unit may weighmore than about 12 g, e.g., up to about 25 g, 45 g, or 90 g.

In some embodiments, the sensor 32 exits the base of the mounting unit14 at a location distant from an edge of the base. In some embodiments,the sensor 32 exits the base of the mounting unit 14 at a locationsubstantially closer to the center than the edges thereof. While notwishing to be bound by theory, it is believed that by providing an exitport for the sensor 32 located away from the edges, the sensor 32 can beprotected from motion between the body and the mounting unit, snaggingof the sensor by an external source, and/or environmental contaminants(e.g., microorganisms) that can migrate under the edges of the mountingunit. In some embodiments, the sensor exits the mounting unit away froman outer edge of the device.

In some alternative embodiments, however, the sensor exits the mountingunit 14 at an edge or near an edge of the device. In some embodiments,the mounting unit is configured such that the exit port (location) ofthe sensor is adjustable; thus, in embodiments wherein the depth of thesensor insertion is adjustable, six-degrees of freedom can thereby beprovided.

Extensible Adhesive Pad

In certain embodiments, an adhesive pad is used with the sensor system.A variety of design parameters are desirable when choosing an adhesivepad for the mounting unit. For example: 1) the adhesive pad can bestrong enough to maintain full contact at all times and during allmovements (devices that release even slightly from the skin have agreater risk of contamination and infection), 2) the adhesive pad can bewaterproof or water permeable such that the host can wear the deviceeven while heavily perspiring, showering, or even swimming in somecases, 3) the adhesive pad can be flexible enough to withstand linearand rotational forces due to host movements, 4) the adhesive pad can becomfortable for the host, 5) the adhesive pad can be easily releasableto minimize host pain, 6) and/or the adhesive pad can be easilyreleasable so as to protect the sensor during release. Unfortunately,these design parameters are difficult to simultaneously satisfy usingknown adhesive pads, for example, strong medical adhesive pads areavailable but are usually non-precise (for example, requiringsignificant “ripping” force during release) and can be painful duringrelease due to the strength of their adhesion.

Therefore, the preferred embodiments provide an adhesive pad 8′ formounting the mounting unit onto the host, including a sufficientlystrong medical adhesive pad that satisfies one or more strength andflexibility requirements described above, and further provides a foreasy, precise and pain-free release from the host's skin. FIG. 10A is aside view of the sensor assembly, illustrating the sensor implanted intothe host with mounting unit adhered to the host's skin via an adhesivepad in one embodiment. Namely, the adhesive pad 8′ is formed from anextensible material that can be removed easily from the host's skin bystretching it lengthwise in a direction substantially parallel to (or upto about 35 degrees from) the plane of the skin. It is believed thatthis easy, precise, and painless removal is a function of both the highextensibility and easy stretchability of the adhesive pad.

In one embodiment, the extensible adhesive pad includes a polymeric foamlayer or is formed from adhesive pad foam. It is believed that theconformability and resiliency of foam aids in conformation to the skinand flexibility during movement of the skin. In another embodiment, astretchable solid adhesive pad, such as a rubber-based or anacrylate-based solid adhesive pad can be used. In another embodiment,the adhesive pad comprises a film, which can aid in increasing loadbearing strength and rupture strength of the adhesive pad

FIGS. 10B to 10C illustrate initial and continued release of themounting unit from the host's skin by stretching the extensible adhesivepad in one embodiment. To release the device, the backing adhesive padis pulled in a direction substantially parallel to (or up to about 35degrees from) the plane of the device. Simultaneously, the extensibleadhesive pad stretches and releases from the skin in a relatively easyand painless manner.

In one implementation, the mounting unit is bonded to the host's skinvia a single layer of extensible adhesive pad 8′, which is illustratedin FIGS. 10A to 10C. The extensible adhesive pad includes asubstantially non-extensible pull-tab 52, which can include a lightadhesive pad layer that allows it to be held on the mounting unit 14prior to release. Additionally, the adhesive pad can further include asubstantially non-extensible holding tab 54, which remains attached tothe mounting unit during release stretching to discourage completeand/or uncontrolled release of the mounting unit from the skin.

In one alternative implementation, the adhesive pad 8′ includestwo-sides, including the extensible adhesive pad and a backing adhesivepad (not shown). In this embodiment, the backing adhesive pad is bondedto the mounting unit's back surface 25 while the extensible adhesive pad8′ is bonded to the host's skin. Both adhesive pads provide sufficientstrength, flexibility, and waterproof or water permeable characteristicsappropriate for their respective surface adhesion. In some embodiments,the backing and extensible adhesive pads are particularly designed withan optimized bond for their respective bonding surfaces (namely, themounting unit and the skin).

In another alternative implementation, the adhesive pad 8′ includes adouble-sided extensible adhesive pad surrounding a middle layer orbacking layer (not shown). The backing layer can comprise a conventionalbacking film or can be formed from foam to enhance comfort,conformability, and flexibility. Preferably, each side of thedouble-sided adhesive pad is respectively designed for appropriatebonding surface (namely, the mounting unit and skin). A variety ofalternative stretch-release configurations are possible. Controlledrelease of one or both sides of the adhesive pad can be facilitated bythe relative lengths of each adhesive pad side, by incorporation of anon-adhesive pad zone, or the like.

FIGS. 11A and 11B are perspective and side cross-sectional views,respectively, of the mounting unit immediately following sensorinsertion and release of the applicator from the mounting unit. In oneembodiment, such as illustrated in FIGS. 11A and 11B, the contactsubassembly 26 is held in its insertion position, substantially at theinsertion angle a of the sensor. Maintaining the contact subassembly 26at the insertion angle a during insertion enables the sensor 32 to beeasily inserted straight through the contact subassembly 26. The contactsubassembly 26 further includes a hinge 38 that allows movement of thecontact subassembly 26 from an angled to a flat position. The term“hinge,” as used herein, is a broad term and is used in its ordinarysense, including, without limitation, a mechanism that allowsarticulation of two or more parts or portions of a device. The term isbroad enough to include a sliding hinge, for example, a ball and detenttype hinging mechanism.

Although the illustrated embodiments describe a fixed insertion angledesigned into the applicator, alternative embodiments can design theinsertion angle into other components of the system. For example, theinsertion angle can be designed into the attachment of the applicatorwith the mounting unit, or the like. In some alternative embodiments, avariety of adjustable insertion angles can be designed into the systemto provide for a variety of host dermis configurations.

FIG. 11B illustrates the sensor 32 extending from the mounting unit 14by a preselected distance, which defines the depth of insertion of thesensor into the host. The dermal and subcutaneous make-up of animals andhumans is variable and a fixed depth of insertion may not be appropriatefor all implantations. Accordingly, in an alternative embodiment, thedistance that the sensor extends from the mounting unit is adjustable toaccommodate a variety of host body-types. For example, the applicator 12can be designed with a variety of adjustable settings, which control thedistance that the needle 72 (and therefore the sensor 32) extends uponsensor insertion. One skilled in the art appreciates a variety of meansand mechanisms can be employed to accommodate adjustable sensorinsertion depths, which are considered within the scope of the preferredembodiments. The preferred insertion depth is from about 0.1 mm or lessto about 2 cm or more, preferably from about 0.15, 0.2, 0.25, 0.3, 0.35,0.4, or 0.45 mm to about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, or 1.9 cm.

FIGS. 12A and 12B are perspective and side cross-sectional views,respectively, of the mounting unit after articulating the contactsubassembly to its functional position (which is also referred to as aninserted, implanted, or sensing position). The hinge 38 enables thecontact subassembly 26 to tilt from its insertion position (FIG. 11) toits functional position (FIG. 12) by pressing downward on the contactsubassembly, for example. Certain embodiments provide this pivotalmovement via two separate pieces (the contact subassembly 26 and themounting unit 14 connected by a hinge, for example, a mechanical oradhesive pad joint or hinge). A variety of pivoting, articulating,and/or hinging mechanisms can be employed with the sensors of preferredembodiments. For example, the hinge can be formed as a part of thecontact subassembly 26. The contact subassembly can be formed from aflexible piece of material (such as silicone, urethane rubber, or otherflexible or elastomeric material), wherein the material is sufficientlyflexible to enable bending or hinging of the contact subassembly from anangle appropriate for insertion (FIGS. 11A and 11B) to a lowerfunctional configuration (FIGS. 12A and 12B).

The relative pivotal movement of the contact subassembly isadvantageous, for example, for enabling the design of a low profiledevice while providing support for an appropriate needle insertionangle. In its insertion position, the sensor system is designed for easysensor insertion while forming a stable electrical connection with theassociated contacts 28. In its functional position, the sensor systemmaintains a low profile for convenience, comfort, and discreetnessduring use. Thus, the sensor systems of preferred embodiments areadvantageously designed with a hinging configuration to provide anoptimum guided insertion angle while maintaining a low profile deviceduring sensor use.

In some embodiments, a shock-absorbing member or feature is incorporatedinto the design of the sensor and configured to absorb movement of thein vivo and/or ex vivo portion of the sensor. Conventional analytesensors can suffer from motion-related artifact associated with hostmovement when the host is using the device. For example, when atranscutaneous analyte sensor is inserted into the host, variousmovements on the sensor (for example, relative movement between the invivo portion and the ex vivo portion and/or movement within the host)create stresses on the device and can produce noise in the sensorsignal. Accordingly in some embodiments, a shock-absorbing member islocated on the sensor/mounting unit in a location that absorbs stressesassociated with the above-described movement.

In the preferred embodiments, the sensor 32 bends from a substantiallystraight to substantially bent configuration upon pivoting of thecontact subassembly from the insertion to functional position. Thesubstantially straight sensor configuration during insertionadvantageously provides ease of sensor insertion, while the substantialbend in the sensor in its functional position advantageously providesstability on the proximal end of the sensor with flexibility/mobility onthe distal end of the sensor. Additionally, motion within the mountingunit (e.g., caused by external forces to the mounting unit, movement ofthe skin, and the like) does not substantially translate to the in vivoportion of the sensor. Namely, the bend formed within the sensor 32functions to break column strength, causing flexion that effectivelyabsorbs movements on the sensor during use. Additionally, the sensor canbe designed with a length such that when the contact subassembly 26 ispivoted to its functional position (FIG. 11B), the sensor pushes forwardand flexes, allowing it to absorb motion between the in vivo and ex vivoportions of the sensor. It is believed that both of the above advantagesminimize motion artifact on the sensor signal and/or minimize damage tothe sensor caused by movement, both of which (motion artifact anddamage) have been observed in conventional transcutaneous sensors.

In some alternative embodiments, the shock-absorbing member can be anexpanding and contracting member, such as a spring, accordion,telescoping, or bellows-type device. In general, the shock absorbingmember can be located such that relative movement between the sensor,the mounting unit, and the host is absorbed without (or minimally)affecting the connection of the sensor to the mounting unit and/or thesensor stability within the implantation site; for example, theshock-absorbing member can be formed as a part of or connected to thesensor 32.

FIGS. 13A to 13C are perspective and side views of a sensor systemincluding the mounting unit 14 and electronics unit 16 attached thereto.After sensor insertion, the transcutaneous analyte sensor system 10measures a concentration of an analyte or a substance indicative of theconcentration or presence of the analyte as described above. Althoughthe examples are directed to a glucose sensor, the analyte sensor can bea sensor capable of determining the level of any suitable analyte in thebody, for example, oxygen, lactase, insulin, hormones, cholesterol,medicaments, viruses, or the like. Once the electronics unit 16 isconnected to the mounting unit 14, the sensor 32 is able to measurelevels of the analyte in the host.

Detachable connection between the mounting unit 14 and electronics unit16 provides improved manufacturability, namely, the relativelyinexpensive mounting unit 14 can be disposed of when replacing thesensor system after its usable life, while the relatively more expensiveelectronics unit 16 can be reusable with multiple sensor systems. Incertain embodiments, the electronics unit 16 is configured withprogramming, for example, initialization, calibration reset, failuretesting, or the like, each time it is initially inserted into the cavityand/or each time it initially communicates with the sensor 32. However,an integral (non-detachable) electronics unit can be configured as isappreciated by one skilled in the art.

Referring to the mechanical fit between the mounting unit 14 and theelectronics unit 16 (and/or applicator 12), a variety of mechanicaljoints are contemplated, for example, snap fit, interference fit, orslide fit. In the illustrated embodiment of FIGS. 13A to 13C, tabs 120are provided on the mounting unit 14 and/or electronics unit 16 thatenable a secure connection therebetween. The tabs 120 of the illustratedembodiment can improve ease of mechanical connection by providingalignment of the mounting unit and electronics unit and additional rigidsupport for force and counter force by the user (e.g., fingers) duringconnection. However, other configurations with or without guiding tabsare contemplated, such as illustrated in FIGS. 11 and 12, for example.

In some circumstances, a drift of the sensor signal can causeinaccuracies in sensor performance and/or require re-calibration of thesensor. Accordingly, it can be advantageous to provide a sealant,whereby moisture (e.g., water and water vapor) cannot substantiallypenetrate to the sensor and its connection to the electrical contacts.The sealant described herein can be used alone or in combination withthe sealing member 36 described in more detail above, to seal the sensorfrom moisture in the external environment.

Preferably, the sealant fills in holes, crevices, or other void spacesbetween the mounting unit 14 and electronics unit 16 and/or around thesensor 32 within the mounting unit 32. For example, the sealant cansurround the sensor in the portion of the sensor 32 that extends throughthe contacts 28. Additionally, the sealant can be disposed within theadditional void spaces, for example a hole 122 that extends through thesealing member 36.

Preferably, the sealant comprises a water impermeable material orcompound, for example, oil, grease, or gel. In one exemplary embodiment,the sealant, which also can be referred to as a lubricant in certainembodiments, comprises petroleum jelly and is used to provide a moisturebarrier surrounding the sensor 32. In one experiment, petroleum jellywas liquefied by heating, after which a sensor 32 was immersed into theliquefied petroleum jelly to coat the outer surfaces thereof. The sensorwas then assembled into a housing and inserted into a host, during whichdeployment the sensor was inserted through the electrical contacts 28and the petroleum jelly conforming therebetween. Sensors incorporatingpetroleum jelly, such as described above, when compared to sensorswithout the petroleum jelly moisture barrier exhibited less or no signaldrift over time when studied in a humid or submersed environment. Whilenot wishing to be bound by theory, it is believed that incorporation ofa moisture barrier surrounding the sensor, especially between the sensorand its associated electrical contacts, reduces or eliminates theeffects of humidity on the sensor signal. The viscosity of grease oroil-based moisture barriers allows penetration into and through evensmall cracks or crevices within the sensor and mounting unit, displacingmoisture and thereby increasing the sealing properties thereof. U.S.Pat. No. 4,259,540 and U.S. Pat. No. 5,285,513 disclose materialssuitable for use as a water impermeable material (sealant).

Referring to the electrical fit between the sensor 32 and theelectronics unit 16, contacts 28 (through which the sensor extends) areconfigured to electrically connect with mutually engaging contacts onthe electronics unit 16. A variety of configurations are contemplated;however, the mutually engaging contacts operatively connect upondetachable connection of the electronics unit 16 with the mounting unit14, and are substantially sealed from external moisture by sealingmember 36. Even with the sealing member, some circumstances can existwherein moisture can penetrate into the area surrounding the sensor 32and or contacts, for example, exposure to a humid or wet environment(e.g., caused by sweat, showering, or other environmental causes). Ithas been observed that exposure of the sensor to moisture can be a causeof baseline signal drift of the sensor over time. For example in aglucose sensor, the baseline is the component of a glucose sensor signalthat is not related to glucose (the amount of signal if no glucose ispresent), which is ideally constant over time. However, somecircumstances my exist wherein the baseline can fluctuate over time,also referred to as drift, which can be caused, for example, by changesin a host's metabolism, cellular migration surrounding the sensor,interfering species, humidity in the environment, and the like.

In some embodiments, the mounting unit is designed to provideventilation (e.g., a vent hole 124) between the exit-site and thesensor. In certain embodiments, a filter (not shown) is provided in thevent hole 124 that allows the passage of air, while preventingcontaminants from entering the vent hole 124 from the externalenvironment. While not wishing to be bound by theory, it is believedthat ventilation to the exit-site (or to the sensor 32) can reduce oreliminate trapped moisture or bacteria, which can otherwise increase thegrowth and/or lifetime of bacteria adjacent to the sensor.

In some alternative embodiments, a sealing material is provided, whichseals the needle and/or sensor from contamination of the externalenvironment during and after sensor insertion. For example, one problemencountered in conventional transcutaneous devices is infection of theexit-site of the wound. For example, bacteria or contaminants canmigrate from ex vivo, for example, any ex vivo portion of the device orthe ex vivo environment, through the exit-site of the needle/sensor, andinto the subcutaneous tissue, causing contamination and infection.Bacteria and/or contaminants can originate from handling of the device,exposed skin areas, and/or leakage from the mounting unit (external to)on the host. In many conventional transcutaneous devices, there existssome path of migration for bacteria and contaminants to the exit-site,which can become contaminated during sensor insertion or subsequenthandling or use of the device. Furthermore, in some embodiments of atranscutaneous analyte sensor, the insertion-aiding device (for example,needle) is an integral part of the mounting unit; namely, the devicestores the insertion device after insertion of the sensor, which isisolated from the exit-site (namely, point-of-entry of the sensor) afterinsertion.

Accordingly, these alternative embodiments provide a sealing material onthe mounting unit, interposed between the housing and the skin, whereinthe needle and/or sensor are adapted to extend through, and be sealedby, the sealing material. The sealing material is preferably formed froma flexible material that substantially seals around the needle/sensor.Appropriate flexible materials include malleable materials, elastomers,gels, greases, or the like (e.g., see U.S. Pat. No. 4,259,540 and U.S.Pat. No. 5,285,513). However, not all embodiments include a sealingmaterial, and in some embodiments a clearance hole or other spacesurrounding the needle and/or sensor is preferred.

In one embodiment, the base 24 of the mounting unit 14 is formed from aflexible material, for example silicone, which by its elastomericproperties seals the needle and/or sensor at the exit port 126, such asis illustrated in FIGS. 12A and 12B. Thus, sealing material can beformed as a unitary or integral piece with the back surface 25 of themounting unit 14, or with an adhesive pad 8 on the back surface of themounting unit, however alternatively can be a separate part secured tothe device. In some embodiments, the sealing material can extend throughthe exit port 126 above or below the plane of the adhesive pad surface,or the exit port 126 can comprise a septum seal such as those used inthe medical storage and disposal industries (for example, silica gelsandwiched between upper and lower seal layers, such as layerscomprising chemically inert materials such as PTFE). A variety of knownseptum seals can be implemented into the exit port of the preferredembodiments described herein. Whether the sealing material is integralwith or a separate part attached to the mounting unit 14, the exit port126 is advantageously sealed so as to reduce or eliminate the migrationof bacteria or other contaminants to or from the exit-site of the woundand/or within the mounting unit.

During use, a host or caretaker positions the mounting unit at theappropriate location on or near the host's skin and prepares for sensorinsertion. During insertion, the needle aids in sensor insertion, afterwhich the needle is retracted into the mounting unit leaving the sensorin the subcutaneous tissue. In this embodiment, the exit-port 126includes a layer of sealing material, such as a silicone membrane, thatencloses the exit-port in a configuration that protects the exit-sitefrom contamination that can migrate from the mounting unit or spacingexternal to the exit-site. Thus, when the sensor 32 and/or needle 72extend through, for example, an aperture or a puncture in the sealingmaterial, to provide communication between the mounting unit andsubcutaneous space, a seal is formed therebetween. Elastomeric sealingmaterials can be advantageous in some embodiments because the elasticityprovides a conforming seal between the needle/sensor and the mountingunit and/or because the elasticity provides shock-absorbing qualitiesallowing relative movement between the device and the various layers ofthe host's tissue, for example.

In some alternative embodiments, the sealing material includes abioactive agent incorporated therein. Suitable bioactive agents includethose which are known to discourage or prevent bacteria and infection,for example, anti-inflammatory, antimicrobials, antibiotics, or thelike. It is believed that diffusion or presence of a bioactive agent canaid in prevention or elimination of bacteria adjacent to the exit-site.

In practice, after the sensor 32 has been inserted into the host'stissue, and an electrical connection formed by mating the electronicsunit 16 to the mounting unit 14, the sensor measures an analyteconcentration continuously or continually, for example, at an intervalof from about fractions of a second to about 10 minutes or more.

FIG. 14 is a perspective view of a sensor system, including wirelesscommunication between a sensor and a receiver. Preferably theelectronics unit 16 is wirelessly connected to a receiver 158 via one-or two-way RF transmissions or the like. However, a wired connection isalso contemplated. The receiver 158 provides much of the processing anddisplay of the sensor data, and can be selectively worn and/or removedat the host's convenience. Thus, the sensor system 10 can be discreetlyworn, and the receiver 158, which provides much of the processing anddisplay of the sensor data, can be selectively worn and/or removed atthe host's convenience. Particularly, the receiver 158 includesprogramming for retrospectively and/or prospectively initiating acalibration, converting sensor data, updating the calibration,evaluating received reference and sensor data, and evaluating thecalibration for the analyte sensor, such as described in more detailwith reference to U.S. Publication No. US-2005-0027463-A1.

FIGS. 15A and 15B are perspective views of a receiver in one preferredembodiment, wherein the receiver, also referred to as a communicationstation, is provided with a docking station for receiving and holdingthe electronics unit (from the sensor assembly) when not in use.Preferably, the electronics unit 16 is detachable from and reusable withmultiple sensor assemblies 10, in multiple applications, such asdescribed herein. This embodiment provides a docking station 98 on thereceiver 158 that enables storage, electrical connection, and/or batteryrecharge, for example, for the electronics unit 16 while not in use on asensor assembly 10. Complementary contacts or pins can be provided onthe electronics unit 16 and the docking station 98 that enable operableconnection therebetween. In some embodiments, the receiver includesprogramming that resets calibration when the electronics unit 16 isdocked on the receiver 158. In some embodiments, the receiver isconfigured to reset states in the battery, such as initializing a new(unused) electronics unit to work with the receiver when the electronicsunit 16 is docked on the receiver 158.

After a sensor's usable life, the host's removes and disposes of thesensor assembly 10, saving the reusable electronics unit 16 for use withanother sensor assembly, which can be a few minutes to a few days later,or more, after disposing of the previous sensor assembly. In somealternative embodiments, the docketing station is provided on analternative communication station other than the receiver, for example apersonal computer, server, personal digital assistant, or the like;wherein the functionality described below can be implemented in asimilar manner. In some embodiments, the receiver is configured to testoperation of the electronics unit by stepping the electrodes throughdifferent current draws and disabling usage of the electronics unit if afailure is detected.

Thus, the described embodiments provide an analyte sensor assembly thatenables a comfortable and reliable system for measuring an analyte levelfor short term applications, e.g., up to 7 days or more, withoutsurgery. After the usable life of the sensor (for example, due to apredetermined expiration, potential infection, or level ofinflammation), the host can remove the sensor and mounting from theskin, dispose of the sensor and mounting unit (preferably saving theelectronics unit for reuse). The reusable electronics unit can beinserted with another sensor assembly or be implanted surgically andthus provide continuous sensor output for short or long periods of timein another application. Data provided by the analyte sensor assembly canbe used to calibrate other sensors, e.g., long term sensors includingthe implantable long term glucose sensor described hereinbelow.

Long Term Sensor

FIG. 16 is an exploded perspective view of one exemplary embodiment of along term continuous glucose sensor 1310A. In this embodiment, thesensor is preferably wholly implanted into the subcutaneous tissue of ahost, such as described in U.S. Publication No. US-2006-0015020-A1; U.S.Publication No. US-2005-0245799-A1; U.S. Publication No.US-2005-0192557-A1; U.S. Publication No. US-2004-0199059-A1; U.S.Publication No. US-2005-0027463-A1; and U.S. Pat. No. 6,001,067. In thisexemplary embodiment, a body 1320 and a sensing region 1321 house theelectrodes 1322 and sensor electronics (see FIG. 17). The threeelectrodes 1322 are operably connected to the sensor electronics (seeFIG. 17) and are covered by a sensing membrane 1323 and a biointerfacemembrane 1324, which are attached by a clip 1325.

In one embodiment, the three electrodes 1322 include a platinum workingelectrode, a platinum counter electrode, and a silver/silver chloridereference electrode. The top ends of the electrodes are in contact withan electrolyte phase (not shown), which is a free-flowing fluid phasedisposed between the sensing membrane 1323 and the electrodes 1322. Thesensing membrane 1323 includes an enzyme, for example, glucose oxidase,and covers the electrolyte phase. The biointerface membrane 1324, suchas described above, covers the sensing membrane 1323 and serves, atleast in part, to protect the sensor 1310A from external forces that canresult in environmental stress cracking of the sensing membrane 1323.U.S. Publication No. US-2005-0112169-A1 describes a biointerfacemembrane that can be used in conjunction with the preferred embodiments.

In one embodiment, the biointerface membrane 1324 generally includes acell disruptive domain most distal from the electrochemically reactivesurfaces and a cell impermeable domain less distal from theelectrochemically reactive surfaces than the cell disruptive domain. Thecell disruptive domain is preferably designed to support tissueingrowth, disrupt contractile forces typically found in a foreign bodyresponse, encourage vascularity within the membrane, and disrupt theformation of a barrier cell layer. The cell impermeable domain ispreferably resistant to cellular attachment, impermeable to cells, andcomposed of a biostable material.

In one embodiment, the sensing membrane 1323 generally provides one ormore of the following functions: 1) supporting tissue ingrowth; 2)protection of the exposed electrode surface from the biologicalenvironment, 3) diffusion resistance (limitation) of the analyte, 4) acatalyst for enabling an enzymatic reaction, 5) limitation or blockingof interfering species, and 6) hydrophilicity at the electrochemicallyreactive surfaces of the sensor interface, such as described in U.S.Publication No. US-2005-0245799-A1. Accordingly, the sensing membrane1323 preferably includes a plurality of domains or layers, for example,an electrolyte domain, an interference domain, an enzyme domain (forexample, glucose oxidase), a resistance domain, and can additionallyinclude an oxygen domain (not shown), and/or a bioprotective domain (notshown), such as described in more detail herein and in U.S. PublicationNo. US-2005-0245799-A1. However, it is understood that a sensingmembrane modified for other devices, for example, by including fewer oradditional domains is within the scope of the preferred embodiments.

In some embodiments, the domains of the biointerface and sensingmembranes are formed from materials such as silicone,polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene,homopolymers, copolymers, terpolymers of polyurethanes, polypropylene(PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF),polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA),polyether ether ketone (PEEK), polyurethanes, cellulosic polymers,polysulfones and block copolymers thereof including, for example,di-block, tri-block, alternating, random and graft copolymers. U.S.Publication No. US-2005-0245799-A1 describes biointerface and sensingmembrane configurations and materials that can be applied to thepreferred embodiments.

In the illustrated embodiment, the counter electrode is provided tobalance the current generated by the species being measured at theworking electrode. In the case of a glucose oxidase based glucosesensor, the species being measured at the working electrode is H₂O₂.Glucose oxidase catalyzes the conversion of oxygen and glucose tohydrogen peroxide and gluconate according to the following reaction:

Glucose+O₂→Gluconate+H₂O₂

The change in H₂O₂ can be monitored to determine glucose concentrationbecause for each glucose molecule metabolized, there is a proportionalchange in the product H₂O₂. Oxidation of H₂O₂ by the working electrodeis balanced by reduction of ambient oxygen, enzyme generated H₂O₂, orother reducible species at the counter electrode. The H₂O₂ produced fromthe glucose oxidase reaction further reacts at the surface of workingelectrode and produces two protons (2H⁺), two electrons (2e⁻), and oneoxygen molecule (O₂).

In one embodiment, a potentiostat is employed to monitor theelectrochemical reaction at the electrochemical cell. The potentiostatapplies a constant potential to the working and reference electrodes todetermine a current value. The current that is produced at the workingelectrode (and flows through the circuitry to the counter electrode) issubstantially proportional to the amount of H₂O₂ that diffuses to theworking electrode. Accordingly, a raw signal can be produced that isrepresentative of the concentration of glucose in the user's body, andtherefore can be utilized to estimate a meaningful glucose value, suchas is described herein.

Sensor Electronics

One example of sensor electronics that may be utilized with either theshort term or long term sensors is depicted in the block diagram of FIG.17, illustrating the electronics 132 associated with the sensor systemin one embodiment. In this embodiment, a potentiostat 134 is shown,which is operably connected to an electrode system (such as describedabove) and provides a voltage to the electrodes, which biases the sensorto enable measurement of an current signal indicative of the analyteconcentration in the host (also referred to as the analog portion). Insome embodiments, the potentiostat includes a resistor (not shown) thattranslates the current into voltage. In some alternative embodiments, acurrent to frequency converter is provided that is configured tocontinuously integrate the measured current, for example, using a chargecounting device.

An A/D converter 136 digitizes the analog signal into a digital signal,also referred to as “counts” for processing. Accordingly, the resultingraw data stream in counts, also referred to as raw sensor data, isdirectly related to the current measured by the potentiostat 134.

A processor module 138 includes the central control unit that controlsthe processing of the sensor electronics 132. In some embodiments, theprocessor module includes a microprocessor, however a computer systemother than a microprocessor can be used to process data as describedherein, for example an ASIC can be used for some or all of the sensor'scentral processing. The processor typically provides semi-permanentstorage of data, for example, storing data such as sensor identifier(ID) and programming to process data streams (for example, programmingfor data smoothing and/or replacement of signal artifacts such as isdescribed in U.S. Publication No. US-2005-0043598-A1). The processoradditionally can be used for the system's cache memory, for example fortemporarily storing recent sensor data. In some embodiments, theprocessor module comprises memory storage components such as ROM, RAM,dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs, flashmemory, or the like.

In some embodiments, the processor module comprises a digital filter,for example, an infinite impulse response (IIR) or finite impulseresponse (FIR) filter, configured to smooth the raw data stream from theA/D converter. Generally, digital filters are programmed to filter datasampled at a predetermined time interval (also referred to as a samplerate). In some embodiments, wherein the potentiostat is configured tomeasure the analyte at discrete time intervals, these time intervalsdetermine the sample rate of the digital filter. In some alternativeembodiments, wherein the potentiostat is configured to continuouslymeasure the analyte, for example, using a current-to-frequency converteras described above, the processor module can be programmed to request adigital value from the A/D converter at a predetermined time interval,also referred to as the acquisition time. In these alternativeembodiments, the values obtained by the processor are advantageouslyaveraged over the acquisition time due the continuity of the currentmeasurement. Accordingly, the acquisition time determines the samplerate of the digital filter. In preferred embodiments, the processormodule is configured with a programmable acquisition time, namely, thepredetermined time interval for requesting the digital value from theA/D converter is programmable by a user within the digital circuitry ofthe processor module. An acquisition time of from about 2 seconds toabout 512 seconds is preferred; however any acquisition time can beprogrammed into the processor module. A programmable acquisition time isadvantageous in optimizing noise filtration, time lag, andprocessing/battery power.

Preferably, the processor module is configured to build the data packetfor transmission to an outside source, for example, an RF transmissionto a receiver as described in more detail below. Generally, the datapacket comprises a plurality of bits that can include a preamble, aunique identifier identifying the electronics unit, the receiver, orboth, (e.g., sensor ID code), data (e.g., raw data, filtered data,and/or an integrated value) and/or error detection or correction.Preferably, the data (transmission) packet has a length of from about 8bits to about 128 bits, preferably about 48 bits; however, larger orsmaller packets can be desirable in certain embodiments. The processormodule can be configured to transmit any combination of raw and/orfiltered data. In one exemplary embodiment, the transmission packetcontains a fixed preamble, a unique ID of the electronics unit, a singlefive-minute average (e.g., integrated) sensor data value, and a cyclicredundancy code (CRC).

In some embodiments, the processor module further comprises atransmitter portion that determines the transmission interval of thesensor data to a receiver, or the like. In some embodiments, thetransmitter portion, which determines the interval of transmission, isconfigured to be programmable. In one such embodiment, a coefficient canbe chosen (e.g., a number of from about 1 to about 100, or more),wherein the coefficient is multiplied by the acquisition time (orsampling rate), such as described above, to define the transmissioninterval of the data packet. Thus, in some embodiments, the transmissioninterval is programmable from about 2 seconds to about 850 minutes, morepreferably from about 30 second to about 5 minutes; however, anytransmission interval can be programmable or programmed into theprocessor module. However, a variety of alternative systems and methodsfor providing a programmable transmission interval can also be employed.By providing a programmable transmission interval, data transmission canbe customized to meet a variety of design criteria (e.g., reducedbattery consumption, timeliness of reporting sensor values, etc.)

Conventional glucose sensors measure current in the nanoAmp range. Incontrast to conventional glucose sensors, the preferred embodiments areconfigured to measure the current flow in the picoAmp range, and in someembodiments, femtoAmps. Namely, for every unit (mg/dL) of glucosemeasured, at least one picoAmp of current is measured. Preferably, theanalog portion of the A/D converter 136 is configured to continuouslymeasure the current flowing at the working electrode and to convert thecurrent measurement to digital values representative of the current. Inone embodiment, the current flow is measured by a charge counting device(e.g., a capacitor). Preferably, a charge counting device provides avalue (e.g., digital value) representative of the current flowintegrated over time (e.g., integrated value). In some embodiments, thevalue is integrated over a few seconds, a few minutes, or longer. In oneexemplary embodiment, the value is integrated over 5 minutes; however,other integration periods can be chosen. Thus, a signal is provided,whereby a high sensitivity maximizes the signal received by a minimalamount of measured hydrogen peroxide (e.g., minimal glucose requirementswithout sacrificing accuracy even in low glucose ranges), reducing thesensitivity to oxygen limitations in vivo (e.g., in oxygen-dependentglucose sensors).

In some embodiments, the electronics unit is programmed with a specificID, which is programmed (automatically or by the user) into a receiverto establish a secure wireless communication link between theelectronics unit and the receiver. Preferably, the transmission packetis Manchester encoded; however, a variety of known encoding techniquescan also be employed.

A battery 144 is operably connected to the sensor electronics 132 andprovides the power for the sensor. In one embodiment, the battery is alithium manganese dioxide battery; however, any appropriately sized andpowered battery can be used (for example, AAA, nickel-cadmium,zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium-ion,zinc-air, zinc-mercury oxide, silver-zinc, and/or hermetically-sealed).In some embodiments, the battery is rechargeable, and/or a plurality ofbatteries can be used to power the system. The sensor can betranscutaneously powered via an inductive coupling, for example. In someembodiments, a quartz crystal 96 is operably connected to the processor138 and maintains system time for the computer system as a whole, forexample for the programmable acquisition time within the processormodule.

Optional temperature probe 140 is shown, wherein the temperature probeis located on the electronics assembly or the glucose sensor itself. Thetemperature probe can be used to measure ambient temperature in thevicinity of the glucose sensor. This temperature measurement can be usedto add temperature compensation to the calculated glucose value.

An RF module 148 is operably connected to the processor 138 andtransmits the sensor data from the sensor to a receiver within awireless transmission 150 via antenna 152. In some embodiments, a secondquartz crystal 154 provides the time base for the RF carrier frequencyused for data transmissions from the RF transceiver. In some alternativeembodiments, however, other mechanisms, such as optical, infraredradiation (IR), ultrasonic, or the like, can be used to transmit and/orreceive data.

In the RF telemetry module of the preferred embodiments, the hardwareand software are designed for low power requirements to increase thelongevity of the device (for example, to enable a life of from about 3to about 24 months, or more) with maximum RF transmittance from the invivo environment to the ex vivo environment for wholly implantablesensors (for example, a distance of from about one to ten meters ormore). Preferably, a high frequency carrier signal of from about 402 MHzto about 433 MHz is employed in order to maintain lower powerrequirements. In some embodiments, the RF module employs a one-way RFcommunication link to provide a simplified ultra low power datatransmission and receiving scheme. The RF transmission can be OOK or FSKmodulated, preferably with a radiated transmission power (EIRP) fixed ata single power level of typically less than about 100 microwatts,preferably less than about 75 microwatts, more preferably less thanabout 50 microwatts, and most preferably less than about 25 microwatts.

Additionally, in wholly implantable devices, the carrier frequency isadapted for physiological attenuation levels, which is accomplished bytuning the RF module in a simulated in vivo environment to ensure RFfunctionality after implantation; accordingly, the preferred glucosesensor can sustain sensor function for 3 months, 6 months, 12 months, or24 months or more.

When a sensor is first implanted into host tissue, the sensor andreceiver are initialized. This is referred to as start-up mode, andinvolves optionally resetting the sensor data and calibrating the sensor32. In selected embodiments (e.g., transcutaneous sensors), mating theelectronics unit 16 to the mounting unit 14 triggers a start-up mode. Inother embodiments, the start-up mode is triggered by the receiver, whichis described in more detail with reference to FIG. 21, below.

Preferably, the electronics unit 16 indicates to the receiver (FIGS. 14and 17) that calibration is to be initialized (or re-initialized). Theelectronics unit 16 transmits a series of bits within a transmitted datapacket wherein a sensor code can be included in the periodictransmission of the device. The status code is used to communicatesensor status to the receiving device. The status code can be insertedinto any location in the transmitted data packet, with or without othersensor information. In one embodiment, the status code is designed to beunique or near unique to an individual sensor, which can be accomplishedusing a value that increments, decrements, or changes in some way afterthe transmitter detects that a sensor has been removed and/or attachedto the transmitter. In an alternative embodiment, the status code can beconfigured to follow a specific progression, such as a BCDinterpretation of a Gray code.

In some embodiments (e.g., transcutaneous sensors), the sensorelectronics 132 are configured to detect a current drop to zero in theworking electrode 44 associated with removal of a sensor 32 from thehost (or the electronics unit 16 from the mounting unit 14), which canbe configured to trigger an increment of the status code. If theincremented value reaches a maximum, it can be designed to roll over to0. In some embodiments, the sensor electronics are configured to detecta voltage change cycle associated with removal and/or re-insertion ofthe sensor, which can be sensed in the counter electrode (e.g., of athree-electrode sensor), which can be configured to trigger an incrementof the status code.

In some embodiments, the sensor electronics 132 can be configured tosend a special value (for example, 0) that indicates that theelectronics unit is not attached when removal of the sensor (orelectronics unit) is detected. This special value can be used to triggera variety of events, for example, to halt display of analyte values.Incrementing or decrementing routines can be used to skip this specialvalue.

Data Smoothing

Typically, an analyte sensor (both short and long term) produces a rawdata signal that is indicative of the analyte concentration of a user.The above described glucose sensor is only one example of an abundanceof analyte sensors that are able to provide a raw data signal outputindicative of the concentration of the analyte of interest. The devicesand methods of the preferred embodiments, including data smoothing,calibration, evaluation, and other data processing, can be applied toraw data obtained from any analyte sensor capable of producing a outputsignal.

Raw data signals received from an analyte sensor can include signalnoise, which degrades the quality of the data. The use of smoothingalgorithms help improve the signal-to-noise ratio in the sensor byreducing signal jitter, for example. One example of a conventional datasmoothing algorithms include finite impulse response filter (FIR), whichis particularly suited for reducing high-frequency noise (see Steil etal. U.S. Pat. No. 6,558,351). Other analyte sensors have utilizedheuristic and moving average type algorithms to accomplish datasmoothing of signal jitter in data signals, for example.

It is advantageous to also reduce signal noise by attenuating transient,low frequency, non-analyte related signal fluctuations (e.g., transientischemia and/or long transient periods of postural effects thatinterfere with sensor function due to lack of oxygen and/or otherphysiological effects).

In one embodiment, this attenuation of transient low frequencynon-analyte related signal noise is accomplished using a recursivefilter. In contrast to conventional non-recursive (e.g., FIR) filters inwhich each computation uses new input data sets, a recursive filter isan equation that uses moving averages as inputs; that is, a recursivefilter includes previous averages as part of the next filtered output.Recursive filters are advantageous at least in part due to theircomputational efficiency.

FIG. 18 is a graph that illustrates data smoothing of a raw data signalin one embodiment. In this embodiment, the recursive filter isimplemented as a digital infinite impulse response filter (IIR) filter,wherein the output is computed using 6 additions and 7 multiplies asshown in the following equation:

${y(n)} = \frac{\begin{matrix}{{a_{0}*{x(n)}} + {a_{1}*{x\left( {n - 1} \right)}} + {a_{2}*{x\left( {n - 2} \right)}} + {a_{3}*x\left( {n - 3} \right)} -} \\{{b_{1}*{y\left( {n - 1} \right)}} - {b_{2}*{y\left( {n - 2} \right)}} - {b_{3}*{y\left( {n - 3} \right)}}}\end{matrix}}{b_{0}}$

This polynomial equation includes coefficients that are dependent onsample rate and frequency behavior of the filter. In this exemplaryembodiment, frequency behavior passes low frequencies up to cyclelengths of 40 minutes, and is based on a 30 second sample rate.

In some embodiments, data smoothing can be implemented in the sensor andthe smoothed data transmitted to a receiver for additional processing.In other embodiments, raw data can be sent from the sensor to a receiverfor data smoothing and additional processing therein. In yet otherembodiments, the sensor is integral with the receiver and therefore notransmission of data is required.

In one exemplary embodiment, where the sensor is an implantable glucosesensor, data smoothing is performed in the sensor to ensure a continuousstream of data. In alternative embodiments, data smoothing can betransmitted from the sensor to the receiver, and the data smoothingperformed at the receiver; however that there can be a risk oftransmit-loss in the radio transmission from the sensor to the receiverwhen the transmission is wireless. For example, in embodiments wherein asensor is implemented in vivo, the raw sensor signal can be moreconsistent within the sensor (in vivo) than the raw signal transmittedto a source (e.g., receiver) outside the body (e.g., if a patient wereto take the receiver off to shower, communication between the sensor andreceiver can be lost and data smoothing in the receiver would haltaccordingly.) Consequently, a multiple point data loss in the filter cantake, for example, anywhere from 25 to 40 minutes for the smoothed datato recover to where it would have been had there been no data loss.

Other systems and methods for data smoothing and/or for detecting and/orreplacing certain sensor data (e.g., signal artifacts or system noise)are described in U.S Publication No. US-2005-0043598-A1.

Receiver

FIGS. 19A to 19D are schematic views of a receiver in first, second,third, and fourth embodiments, respectively. A receiver 1640 comprisessystems necessary to receive, process, and display sensor data from ananalyte sensor, such as described elsewhere herein. Particularly, thereceiver 1640 can be a pager-sized device, for example, and comprise auser interface that has a plurality of buttons 1642 and a liquid crystaldisplay (LCD) screen 1644, and which can include a backlight. In someembodiments the user interface can also include a keyboard, a speaker,and a vibrator such as described with reference to FIG. 20A.

In some embodiments a user is able to toggle through some or all of thescreens shown in FIGS. 19A to 19D using a toggle button on the receiver.In some embodiments, the user is able to interactively select the typeof output displayed on their user interface. In some embodiments, thesensor output can have alternative configurations.

FIG. 20A is a block diagram that illustrates the configuration of themedical device in one embodiment, including a continuous analyte sensor,a receiver, and an external device. In general, the analyte sensorsystem is any sensor configuration that provides an output signalindicative of a concentration of an analyte (e.g., invasive,minimally-invasive, and/or non-invasive sensors as described above). Theoutput signal is sent to a receiver 158 and received by an input module174, which is described in more detail below. The output signal istypically a raw data stream that is used to provide a useful value ofthe measured analyte concentration to a patient or a doctor, forexample. In some embodiments, the raw data stream can be continuously orperiodically algorithmically smoothed or otherwise modified to diminishoutlying points that do not accurately represent the analyteconcentration, for example due to signal noise or other signalartifacts, such as described in U.S. Pat. No. 6,931,327.

Referring again to FIG. 20A, the receiver 158, which is operativelylinked to the sensor system 10, receives a data stream from the sensorsystem 10 via the input module 174. In one embodiment, the input moduleincludes a quartz crystal operably connected to an RF transceiver (notshown) that together function to receive and synchronize data streamsfrom the sensor system 10. However, the input module 174 can beconfigured in any manner that is capable of receiving data from thesensor. Once received, the input module 174 sends the data stream to aprocessor 176 that processes the data stream, such as is described inmore detail below.

The processor 176 is the central control unit that performs theprocessing, such as storing data, analyzing data streams, calibratinganalyte sensor data, estimating analyte values, comparing estimatedanalyte values with time corresponding measured analyte values,analyzing a variation of estimated analyte values, downloading data, andcontrolling the user interface by providing analyte values, prompts,messages, warnings, alarms, or the like. The processor includes hardwareand software that performs the processing described herein, for exampleflash memory provides permanent or semi-permanent storage of data,storing data such as sensor ID, receiver ID, and programming to processdata streams (for example, programming for performing estimation andother algorithms described elsewhere herein) and random access memory(RAM) stores the system's cache memory and is helpful in dataprocessing.

Preferably, the input module 174 or processor module 176 performs aCyclic Redundancy Check (CRC) to verify data integrity, with or withouta method of recovering the data if there is an error. In someembodiments, error correction techniques such as those that use Hammingcodes or Reed-Solomon encoding/decoding methods are employed to correctfor errors in the data stream. In one alternative embodiment, aniterative decoding technique is employed, wherein the decoding isprocessed iteratively (e.g., in a closed loop) to determine the mostlikely decoded signal. This type of decoding can allow for recovery of asignal that is as low as 0.5 dB above the noise floor, which is incontrast to conventional non-iterative decoding techniques (such asReed-Solomon), which requires approximately 3 dB or about twice thesignal power to recover the same signal (e.g., a turbo code).

An output module 178, which is integral with and/or operativelyconnected with the processor 176, includes programming for generatingoutput based on the data stream received from the sensor system 10 andits processing incurred in the processor 176. In some embodiments,output is generated via a user interface 160.

The user interface 160 comprises a keyboard 162, speaker 164, vibrator166, backlight 168, liquid crystal display (LCD) screen 170, and one ormore buttons 172. The components that comprise the user interface 160include controls to allow interaction of the user with the receiver. Thekeyboard 162 can allow, for example, input of user information abouthimself/herself, such as mealtime, exercise, insulin administration,customized therapy recommendations, and reference analyte values. Thespeaker 164 can produce, for example, audible signals or alerts forconditions such as present and/or estimated hyperglycemic orhypoglycemic conditions in a person with diabetes. The vibrator 166 canprovide, for example, tactile signals or alerts for reasons such asdescribed with reference to the speaker, above. The backlight 168 can beprovided, for example, to aid the user in reading the LCD 170 in lowlight conditions. The LCD 170 can be provided, for example, to providethe user with visual data output, such as is described in U.S.Publication No. US-2005-0203360-A1. FIGS. 20B to 20D illustrate someadditional visual displays that can be provided on the screen 170. Insome embodiments, the LCD is a touch-activated screen, enabling eachselection by a user, for example, from a menu on the screen. The buttons172 can provide for toggle, menu selection, option selection, modeselection, and reset, for example. In some alternative embodiments, amicrophone can be provided to allow for voice-activated control.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as reference outliervalues, requests for reference analyte values, therapy recommendations,deviation of the measured analyte values from the estimated analytevalues, or the like. Additionally, prompts can be displayed to guide theuser through calibration or trouble-shooting of the calibration.

In some embodiments, the receiver and/or a device connected to thereceiver is configured to audibly output the user's analyte value(s),trend information (increasing or decreasing analyte values), and thelike, hereinafter referred to as the audible output module. In someembodiments, the audible output module additionally includes: high andlow blood glucose limits at which the module will audibly output theuser's analyte value and/or trend information; English and non-Englishlanguage versions; and choice of male or female voice. In someembodiments, the audible output is transmitted to an earbud worn by thepatient for use where privacy is required or by a patient who issomewhat audibly impaired. The audible output module can be particularlyadvantageous in applications wherein the user is visually and/or hearingimpaired, or is unable to visually check their receiver due to othercircumstances (e.g., operating a motor vehicle or machinery, engaged ina business meeting or social event, or the like).

Additionally, data output from the output module 178 can provide wiredor wireless, one- or two-way communication between the receiver 158 andan external device 180. The external device 180 can be any device thatwherein interfaces or communicates with the receiver 158. In someembodiments, the external device 180 is a computer, and the receiver 158is able to download historical data for retrospective analysis by thepatient or physician, for example. In some embodiments, the externaldevice 180 is a modem or other telecommunications station, and thereceiver 158 is able to send alerts, warnings, emergency messages, orthe like, via telecommunication lines to another party, such as a doctoror family member. In some embodiments, the external device 180 is aninsulin pen, and the receiver 158 is able to communicate therapyrecommendations, such as insulin amount and time to the insulin pen. Insome embodiments, the external device 180 is an insulin pump, and thereceiver 158 is able to communicate therapy recommendations, such asinsulin amount and time to the insulin pump. The external device 180 caninclude other technology or medical devices, for example pacemakers,implanted analyte sensor patches, other infusion devices, telemetrydevices, or the like.

The user interface 160, including keyboard 162, buttons 172, amicrophone (not shown), and the external device 180, can be configuredto allow input of data. Data input can be helpful in obtaininginformation about the patient (for example, meal time, exercise, or thelike), receiving instructions from a physician (for example, customizedtherapy recommendations, targets, or the like), and downloading softwareupdates, for example. Keyboard, buttons, touch-screen, and microphoneare all examples of mechanisms by which a user can input data directlyinto the receiver. A server, personal computer, personal digitalassistant, insulin pump, and insulin pen are examples of externaldevices that can provide useful information to the receiver. Otherdevices internal or external to the sensor that measure other aspects ofa patient's body (for example, temperature sensor, accelerometer, heartrate monitor, oxygen monitor, or the like) can be used to provide inputhelpful in data processing. In one embodiment, the user interface canprompt the patient to select an activity most closely related to theirpresent activity, which can be helpful in linking to an individual'sphysiological patterns, or other data processing. In another embodiment,a temperature sensor and/or heart rate monitor can provide informationhelpful in linking activity, metabolism, and glucose excursions of anindividual. While a few examples of data input have been provided here,a variety of information can be input, which can be helpful in dataprocessing.

FIG. 20B is an illustration of an LCD screen 170 showing continuous andsingle point glucose information in the form of a trend graph 184 and asingle numerical value 186. The trend graph shows upper and lowerboundaries 182 representing a target range between which the host shouldmaintain his/her glucose values. Preferably, the receiver is configuredsuch that these boundaries 182 can be configured or customized by auser, such as the host or a care provider. By providing visualboundaries 182, in combination with continuous analyte values over time(e.g., a trend graph 184), a user can better learn how to controlhis/her analyte concentration (e.g., a person with diabetes can betterlearn how to control his/her glucose concentration) as compared tosingle point (single numerical value 186) alone. Although FIG. 20Billustrates a 1 hour trend graph (e.g., depicted with a time range 188of 1 hour), a variety of time ranges can be represented on the screen170, for example, 3 hour, 9 hour, 1 day, and the like.

FIG. 20C is an illustration of an LCD screen 170 showing a low alertscreen that can be displayed responsive to a host's analyteconcentration falling below a lower boundary (see boundaries 182). Inthis exemplary screen, a host's glucose concentration has fallen to 55mg/dL, which is below the lower boundary set in FIG. 20B, for example.The arrow 190 represents the direction of the analyte trend, forexample, indicating that the glucose concentration is continuing todrop. The annotation 192 (“LOW”) is helpful in immediately and clearlyalerting the host that his/her glucose concentration has dropped below apreset limit, and what may be considered to be a clinically safe value,for example. FIG. 20D is an illustration of an LCD screen 170 showing ahigh alert screen that can be displayed responsive to a host's analyteconcentration rising above an upper boundary (see boundaries 182). Inthis exemplary screen, a host's glucose concentration has risen to 200mg/dL, which is above a boundary set by the host, thereby triggering thehigh alert screen. The arrow 190 represents the direction of the analytetrend, for example, indicating that the glucose concentration iscontinuing to rise. The annotation 192 (“HIGH”) is helpful inimmediately and clearly alerting the host that his/her glucoseconcentration has above a preset limit, and what may be considered to bea clinically safe value, for example.

Although a few exemplary screens are depicted herein, a variety ofscreens can be provided for illustrating any of the informationdescribed in the preferred embodiments, as well as additionalinformation. A user can toggle between these screens (e.g., usingbuttons 172) and/or the screens can be automatically displayedresponsive to programming within the receiver 158, and can besimultaneously accompanied by another type of alert (audible or tactile,for example).

In some embodiments the receiver 158 can have a length of from about 8cm to about 15 cm, a width of from about 3.5 cm to about 10 cm, and/or athickness of from about 1 cm to about 3.5 cm. In some embodiments thereceiver 158 can have a volume of from about 120 cm³ to about 180 cm³,and can have a weight of from about 70 g to 130 g. The dimensions andvolume can be higher or lower, depending, e.g., on the type of devicesintegrated (e.g., finger stick devices, pumps, PDAs, and the like.), thetype of user interface employed, and the like.

In some embodiments, the receiver 158 is an application-specific device.In some embodiments the receiver 158 can be a device used for otherfunctions, such as are described in U.S. Pat. No. 6,558,320. Forexample, the receiver 158 can be integrated into a personal computer(PC), a personal digital assistant (PDA), a cell phone, or another fixedor portable computing device. The integration of the receiver 158function into a more general purpose device can comprise the addition ofsoftware and/or hardware to the device. Communication between the sensorelectronics 16 and the receiver 158 function of the more general purposedevice can be implemented with wired or wireless technologies. Forexample, a PDA can be configured with a data communications port and/ora wireless receiver. After the user establishes a communication linkbetween the electronics unit 16 and the PDA, the electronics unit 16transmits data to the PDA which then processes the data according tosoftware which has been loaded thereon so as to display.

Sensor Calibration

Reference is now made to FIG. 21, which is a flow chart that illustratesthe initial calibration and data output of sensor data from a sensor,e.g., a short term or long term analyte sensor. Calibration of ananalyte sensor comprises data processing that uses sensor data and otherinformation to determine an estimated analyte measurement that ismeaningful to a user or useful for further data processing. One or morereference values can be used to calibrate the sensor data. In someembodiments, reference values can be obtained from sensor data ofanother analyte sensor. For example, a substantially continuous shortterm sensor can be used to calibrate another substantially continuousshort term sensor or a substantially continuous long term sensor, or asubstantially continuous long term sensor can be used to calibrateanother substantially continuous long term sensor or a substantiallycontinuous short term sensor. Reference values can also be obtained froma non-continuous monitoring system, such as a self-monitored bloodanalyte test (e.g., finger stick blood samples), an optical sensor, etc.However, using sensor data from an already employed substantiallycontinuous short term sensor or a substantially continuous long termsensor can reduce or obviate the need for non-continuous manualmeasurements to obtain reference data. In addition, reference values canbe obtained from in-vitro benchtop sources during a benchtop calibrationprocess. For example, reference solutions of analyte may be used forin-vitro calibration where the reference value for the concentration isknown from the reference solution preparation.

FIG. 21 illustrates initial calibration of an analyte sensor usingreference data from any reference analyte source, including anotheranalyte sensor (for example, a previously calibrated analyte sensor). Atblock 261, a sensor data receiving module, also referred to as thesensor data module, receives sensor data (e.g., a data stream),including one or more time-spaced sensor data points, from a sensor viathe receiver, which can be in wired or wireless communication with thesensor. The sensor data point(s) can be smoothed, such as described withreference to FIG. 18, above. During the initialization of the sensor,prior to initial calibration, the receiver (e.g., computer system)receives and stores the sensor data. However, the receiver can beconfigured so that data is not displayed to a user until initialcalibration and possibly stabilization of the sensor has beendetermined.

At block 262, a reference data receiving module, also referred to as thereference input module, receives reference data from a reference analytesource, including one or more reference data points. In one embodiment,the reference data is based on sensor data from another substantiallycontinuous analyte sensor, e.g., an analyte sensor described herein, oranother type of suitable analyte sensor. For example, a previouslycalibrated short or long term glucose sensor providing sensor data for ahost can provide reference data for use in calibrating sensor data froma long term glucose sensor implanted in the same host.

At block 263, a data matching module, also referred to as the processormodule, matches reference data (e.g., one or more reference analyte datapoints) with substantially time corresponding sensor data (e.g., one ormore sensor data points) to provide one or more matched data pairs. Inone embodiment, one reference data point is matched to one timecorresponding sensor data point to form a matched data pair. In anotherembodiment, a plurality of reference data points are averaged (e.g.,equally or non-equally weighted average, mean-value, median, or thelike) and matched to one time corresponding sensor data point to form amatched data pair. In another embodiment, one reference data point ismatched to a plurality of time corresponding sensor data points averagedto form a matched data pair. In yet another embodiment, a plurality ofreference data points are averaged and matched to a plurality of timecorresponding sensor data points averaged to form a matched data pair.In yet another embodiment, a line is produced from the reference datapoints as a function of time. The line may be produced by connectingindividual data points, from smoothed data points, or as a best-fitthrough the application of an appropriate algorithm. A line producedfrom a series of sensor data points may be matched to the line producedfrom the reference data points.

To properly associate the sensor data with reference data, a delay inthe sensing process can be taken into account. In one embodiment, thereference data is provided by another substantially continuous sourcethat has similar sensor characteristics so that the delay in the sensordata is similar to the delay in the reference data. If the delay is notsimilar, the data can be appropriately processed to associate the datataken at the same time. In one embodiment where the sensor data is beingassociated with data from a non-continuous source, time correspondingsensor data comprises one or more sensor data points that occur 5 min(e.g., +/−2½ minutes) after the reference analyte data timestamp (e.g.,the time that the reference analyte data is obtained). In thisembodiment, the 15 minute time delay has been chosen to account for anapproximately 10 minute delay introduced by the filter used in datasmoothing and an approximately 5 minute physiological time-lag (e.g.,the time necessary for the analyte to diffusion through a membrane(s) ofan analyte sensor). In alternative embodiments, the time correspondingsensor value can be more or less than the above-described embodiment,for example ±60 minutes. Variability in time correspondence of sensorand reference data can be attributed to, for example a longer or shortertime delay introduced by the data smoothing filter, or if theconfiguration of the analyte sensor incurs a greater or lesserphysiological time lag. In one exemplary embodiment, time delayinformation from a short term sensor can be used by a long term sensoras described above. In another exemplary embodiment, time delayinformation from a first short term sensor can be used by a second shortterm sensor as described above. In yet another exemplary embodiment,time delay information from a first long term sensor can be used by asecond long term sensor as described above.

In some embodiments, tests are used to evaluate the best matched pairusing a reference data point against individual sensor values over apredetermined time period (e.g., about 30 minutes). In one suchexemplary embodiment, the reference data point is matched with sensordata points at 5-minute intervals and each matched pair is evaluated.The matched pair with the best correlation can be selected as thematched pair for data processing. In some alternative embodiments,matching a reference data point with an average of a plurality of sensordata points over a predetermined time period can be used to form amatched pair.

At block 264, a calibration set module, also referred to as theprocessor module, forms an initial calibration set from a set of one ormore matched data pairs, which are used to determine the relationshipbetween the reference analyte data and the sensor analyte data, such aswill be described in more detail with reference to block 267, below.

The matched data pairs, which make up the initial calibration set, canbe selected according to predetermined criteria. The criteria for theinitial calibration set can be the same as, or different from, thecriteria for the update calibration set, which is described in moredetail with reference to FIG. 24. In some embodiments, the number (n) ofdata pair(s) selected for the initial calibration set is one. In otherembodiments, n data pairs are selected for the initial calibration setwherein n is a function of the frequency of the received reference datapoints. For example, a substantially continuous analyte sensor canprovide numerous data points for use as reference data (e.g., dozens oreven hundreds). In one exemplary embodiment, a substantially continuousanalyte sensor provides about 288 reference data points per day (aboutevery five minutes for twenty-four hours). In one exemplary embodiment,six data pairs make up the initial calibration set.

In some embodiments, the data pairs are selected only within a certainanalyte value threshold, for example wherein the reference analyte valueis from about 40 and to about 400 mg/dL. In some embodiments, the datapairs that form the initial calibration set are selected according totheir time stamp. In some embodiments, the calibration set is selectedsuch as described with reference to FIG. 24.

At block 265, an optional stability determination module, also referredto as the start-up module, determines the stability of the analytesensor over a period of time. Some analyte sensors can have an initialinstability time period during which the analyte sensor is unstable forenvironmental, physiological, or other reasons. One example of initialsensor instability is an embodiment wherein the analyte sensor isimplanted subcutaneously; in this example embodiment, stabilization ofthe analyte sensor can be dependent upon the maturity of the tissueingrowth around and within the sensor. Another example of initial sensorinstability is in an embodiment wherein the analyte sensor is insertedtransdermally (e.g., transcutaneously); in this example embodiment,stabilization of the analyte sensor can be dependent upon electrodestabilization and/or sweat, for example.

Accordingly, in some embodiments, determination of sensor stability caninclude waiting a predetermined time period (e.g., an implantable sensoris known to require a time period for tissue ingrowth, and a transdermal(e.g., transcutaneous) sensor is known to require time to equilibratethe sensor with the user's tissue); in some embodiments, this waitingperiod is from about one minute to about six weeks. Although in someembodiments, the sensitivity (e.g., sensor signal strength with respectto analyte concentration) can be used to determine the stability of thesensor; for example, amplitude and/or variability of sensor sensitivitycan be evaluated to determine the stability of the sensor. Inalternative embodiments, detection of pH levels, oxygen, hypochlorite,interfering species (e.g., ascorbate, urea, and acetaminophen),correlation between sensor and reference values (e.g., R-value),baseline drift and/or offset, and the like can be used to determine thestability of the sensor. In one exemplary embodiment, wherein the sensoris a glucose sensor, it is known to provide a signal that is associatedwith interfering species (e.g., ascorbate, urea, acetaminophen), whichcan be used to evaluate sensor stability. In another exemplaryembodiment, wherein the sensor is a glucose sensor such as describedwith reference to FIGS. 8 and 9, the counter electrode can be monitoredfor oxygen deprivation, which can be used to evaluate sensor stabilityor functionality. Numerous other systems and methods for evaluatingsensor stability or functionality are described in U.S. Publication No.US-2005-0043598-A1. In one embodiment employing a long term implantablesensor that requires a waiting period, a short term sensor or a seriesof short term sensors employed for the same user provides sensor data tothe user during the waiting period. In an embodiment employing a seriesof short term sensors, the sensors can be employed so that they providesensor data in discrete or overlapping periods. In such embodiments, thesensor data from one short term sensor can be used to calibrate anothershort term sensor, or be used to confirm the validity of a subsequentlyemployed short term sensor. The data can also be used for calibratingthe implantable long term sensor so that data from the long term sensorcan be used immediately upon completion of the waiting period.

At decision block 266, the system (e.g., microprocessor) determineswhether the analyte sensor is sufficiently stable according to certaincriteria, such as described above. In one embodiment wherein the sensoris an implantable glucose sensor, the system waits a predetermined timeperiod believed necessary for sufficient tissue ingrowth and evaluatesthe sensor sensitivity (e.g., from about one minute to about six weeks).In another embodiment, the receiver determines sufficient stabilitybased on oxygen concentration near the sensor head. In yet anotherembodiment, the sensor determines sufficient stability based on areassessment of baseline drift and/or offset. A few examples ofdetermining sufficient stability are given here, however a variety ofknown tests and parameters can be used to determine sensor stabilitywithout departing from the spirit and scope of the preferredembodiments.

If the receiver does not assess that the stability of the sensor issufficient, then the processing returns to block 261, wherein thereceiver receives sensor data such as described in more detail above.The above-described steps are repeated until sufficient stability isdetermined.

If the receiver does assess that the stability of the sensor issufficient, then processing continues to block 267 and the calibrationset is used to calibrate the sensor.

At block 267, the conversion function module uses the calibration set tocreate a conversion function. The conversion function substantiallydefines the relationship between the reference analyte data and theanalyte sensor data.

A variety of known methods can be used with the preferred embodiments tocreate the conversion function from the calibration set. In oneembodiment, wherein a plurality of matched data points form the initialcalibration set, a linear least squares regression is performed on theinitial calibration set such as described with reference to FIG. 14A.

FIG. 22A is a graph that illustrates a regression performed on acalibration set to create a conversion function in one exemplaryembodiment. In this embodiment, a linear least squares regression isperformed on the initial calibration set. The x-axis representsreference analyte data; the y-axis represents sensor data. The graphpictorially illustrates regression of the matched pairs 276 in thecalibration set. Regression calculates a slope 272 and an offset 274(y=mx+b), which defines the conversion function.

In alternative embodiments other algorithms could be used to determinethe conversion function, for example forms of linear and non-linearregression, for example fuzzy logic, neural networks, piece-wise linearregression, polynomial fit, genetic algorithms, and other patternrecognition and signal estimation techniques.

In yet other alternative embodiments, the conversion function cancomprise two or more different optimal conversions to account foroptimal conversion variability due to dependence on parameters, such astime of day, calories consumed, exercise, or analyte concentration aboveor below a set threshold, for example. In one such exemplary embodiment,the conversion function is adapted for the estimated glucoseconcentration (e.g., high vs. low). For example, in an implantableglucose sensor, it has been observed that the cells surrounding theimplant will consume at least a small amount of glucose as it diffusestoward the glucose sensor. Assuming the cells consume substantially thesame amount of glucose whether the glucose concentration is low or high,this phenomenon will have a greater effect on the concentration ofglucose during low blood sugar episodes than the effect on theconcentration of glucose during relatively higher blood sugar episodes.Accordingly, the conversion function is adapted to compensate for thesensitivity differences in blood sugar level. In one implementation, theconversion function comprises two different regression lines wherein afirst regression line is applied when the estimated blood glucoseconcentration is at or below a certain threshold (e.g., 150 mg/dL) and asecond regression line is applied when the estimated blood glucoseconcentration is at or above a certain threshold (e.g., 150 mg/dL). Inone alternative implementation, a predetermined pivot of the regressionline that forms the conversion function can be applied when theestimated blood is above or below a set threshold (e.g., 150 mg/dL),wherein the pivot and threshold are determined from a retrospectiveanalysis of the performance of a conversion function and its performanceat a range of glucose concentrations. In another implementation, theregression line that forms the conversion function is pivoted about apoint in order to comply with clinical acceptability standards (e.g.,Clarke Error Grid, Consensus Grid, mean absolute relative difference, orother clinical cost function). Although only a few exampleimplementations are described, the preferred embodiments contemplatenumerous implementations where the conversion function is adaptivelyapplied based on one or more parameters that can affect the sensitivityof the sensor data over time.

In some alternative embodiments, the sensor is calibrated with asingle-point through the use of a dual-electrode system to simplifysensor calibration. In one such dual-electrode system, a first electrodefunctions as a hydrogen peroxide sensor including a membrane systemcontaining glucose-oxidase disposed thereon, which operates as describedherein. A second electrode is a hydrogen peroxide sensor that isconfigured similar to the first electrode, but with a modified membranesystem (with the enzyme domain removed, for example). This secondelectrode provides a signal composed mostly of the baseline signal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx with a single paired measurement. Calibration of the implantedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. U.S.Publication No. US-2005-0143635-A1 describes systems and methods forsubtracting the baseline from a sensor signal.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g., without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g., without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some alternative embodiments, a regression equation y=mx+b is used tocalculate the conversion function; however, prior information can beprovided for m and/or b, thereby enabling calibration to occur withfewer paired measurements. In one calibration technique, priorinformation (e.g., obtained from in vivo or in vitro tests) determines asensitivity of the sensor and/or the baseline signal of the sensor byanalyzing sensor data from measurements taken by the sensor (e.g., priorto inserting the sensor). For example, if there exists a predictiverelationship between in vitro sensor parameters and in vivo parameters,then this information can be used by the calibration procedure. Forexample, if a predictive relationship exists between in vitrosensitivity and in vivo sensitivity, m≈f(m_(in vitro)), then thepredicted m can be used, along with a single matched pair, to solve forb (b=y−mx). If, in addition, b can be assumed to be 0, for example witha dual-electrode configuration that enables subtraction of the baselinefrom the signal such as described above, then both m and b are known apriori, matched pairs are not needed for calibration, and the sensor canbe completely calibrated e.g. without the need for reference analytevalues (e.g. values obtained after implantation in vivo.)

In another alternative embodiment, prior information can be provided toguide or validate the baseline (b) and/or sensitivity (m) determinedfrom the regression analysis. In this embodiment, boundaries can be setfor the regression line that defines the conversion function such thatworking sensors are calibrated accurately and easily (with two points),and non-working sensors are prevented from being calibrated. If theboundaries are drawn too tightly, a working sensor may not enter intocalibration. Likewise, if the boundaries are drawn too loosely, thescheme can result in inaccurate calibration or can permit non-workingsensors to enter into calibration. For example, subsequent to performingregression, the resulting slope and/or baseline are tested to determinewhether they fall within a predetermined acceptable threshold(boundaries). These predetermined acceptable boundaries can be obtainedfrom in vivo or in vitro tests (e.g., by a retrospective analysis ofsensor sensitivities and/or baselines collected from a set ofsensors/patients, assuming that the set is representative of futuredata).

If the slope and/or baseline fall within the predetermined acceptableboundaries, then the regression is considered acceptable. Alternatively,if the slope and/or baseline fall outside the predetermined acceptableboundaries, steps can be taken to either correct the regression orfail-safe such that a system will not process or display errant data.This can be useful in situations wherein regression results in errantslope or baseline values. For example, when points (matched pairs) usedfor regression are too close in value, the resulting regressionstatistically is less accurate than when the values are spread fartherapart. As another example, a sensor that is not properly deployed or isdamaged during deployment can yield a skewed or errant baseline signal.

FIG. 22B is a graph that illustrates one example of using priorinformation for slope and baseline. The x-axis represents referenceglucose data (blood glucose) from a reference glucose source in mg/dL;the y-axis represents sensor data from a transcutaneous glucose sensorof the preferred embodiments in counts. An upper boundary line 215 is aregression line that represents an upper boundary of “acceptability” inthis example; the lower boundary line 216 is a regression line thatrepresents a lower boundary of “acceptability” in this example. Theboundary lines 215, 216 were obtained from retrospective analysis of invivo sensitivities and baselines of glucose sensors as described in thepreferred embodiments.

A plurality of matched data pairs 217 represent data pairs in acalibration set obtained from a glucose sensor as described in thepreferred embodiments. The matched data pairs are plotted according totheir sensor data and time-corresponding reference glucose data. Aregression line 218 represents the result of regressing the matched datapairs 217 using least squares regression. In this example, theregression line falls within the upper and lower boundaries 215, 216indicating that the sensor calibration is acceptable.

However, if the slope and/or baseline had fallen outside thepredetermined acceptable boundaries, which would be illustrated in thisgraph by a line that crosses the upper and/or lower boundaries 215, 216,then the system may be configured to assume a preset baseline value andre-run the regression (or a modified version of the regression) with theassumed baseline, where the assumed baseline value is derived from invivo or in vitro testing. Subsequently, the newly derived slope andbaseline are again tested to determine whether they fall within thepredetermined acceptable boundaries. The processing continues inresponse to the results of the boundary test in a similar fashion. Ingeneral, for a set of matched pairs (e.g., a calibration set),regression lines with higher slope (sensitivity) have a lower baselinewhile regression lines with lower slope (sensitivity) have a higherbaseline. Accordingly, the step of assuming a baseline and testingagainst boundaries can be repeated using a variety of different assumedbaselines based on the baseline, sensitivity, in vitro testing, and/orin vivo testing. For example, if a boundary test fails due to highsensitivity, then a higher baseline is assumed and the regression re-runand boundary-tested. It is preferred that after about two iterations ofassuming a baseline and/or sensitivity and running a modifiedregression, the system assumes an error has occurred (if the resultingregression lines fall outside the boundaries) and fail-safe. The term“fail-safe” includes modifying the system processing and/or display ofdata responsive to a detected error to avoid reporting of inaccurate orclinically irrelevant analyte values.

In yet another alternative embodiment, information obtained prior tosensor insertion can be provided for selecting the baseline (b) and/orslope (m) determined from the regression analysis. For example, adistribution of slopes and/or baselines typically obtained may bedetermined (or estimated) from retrospective analysis of a sample set ofimplanted sensors. This prior distribution information may be used toenable the sensor system to select a preferred combination of slopeand/or baseline to be used in calibration.

In some embodiments, when one or more matched pairs are obtained from asensor implanted in a host (as described elsewhere herein), a pluralityof possible calibration lines can be drawn dependent upon the method ofutilizing these matched pairs to draw a calibration line. For example,where only a single matched pair is obtained, numerous calibration lineshaving various baselines and slopes may be drawn through the singlematched pair. The single matched pair alone does not provide enoughinformation to determine the best calibration line. Similarly, wheremultiple matched pairs are obtained that are clustered closely together,numerous calibration lines may be drawn that pass close to all of thematched pairs in the cluster (e.g., numerous calibration lines aresimilarly correlated with the matched pairs). In some circumstances,some of these multiple calibration lines may not represent the bestcalibration (e.g., due to error in the reference glucose, smalldistribution of pairs, only one matched pair, and the like).Accordingly, in one embodiment, prior information regarding the typicaldistribution of slopes and/or baselines may be used to select one of themultiple calibration lines.

In one embodiment, a baseline can be selected, during calibration, basedon the prior distribution information described above (e.g., byselecting the most probable baseline from the distribution ofbaselines). In another embodiment, a slope can be selected, duringcalibration, based on the prior distribution information described above(e.g., by selecting the most probable slope from the distribution ofslopes). In a preferred embodiment, both a baseline and slope areselected, during calibration, based on the prior distributioninformation described above. For example, in one embodiment, of thepossible multiple calibration lines, the calibration line is chosen thathas a slope and baseline closest to the maximum joint probability ofboth the slope and baseline distributions. In some embodiments,preference may be given to either the slope or baseline such that havingeither a slope or baseline closer to its most probable value is weightedmore heavily.

In one embodiment, depicted in FIG. 22C, the slope and baseline closestto the maximum joint probability may be determined geometrically (e.g.,when both the slope and baseline have normal distributions). In FIG.22C, each slope and baseline determined (or estimated) fromretrospective analysis is plotted as a matched pair 230 in aslope-baseline plot. The set of matched pairs 230 form a clouddistribution, with the center of highest density corresponding to thehighest probability of slope and baseline combination. The set ofpossible calibration lines for the sensor to be calibrated (e.g., fromregression of a single matched pair or set of closely spaced matchedpairs) make up a line 232 in the slope-baseline plot. In one embodiment,the point on this line 234 closest to the center of highest matched pair230 density may be chosen as providing the slope and baseline of theselected calibration line. Either the slope or the baselineprobabilities may be given preference by scaling the cloud distributionalong either the baseline or slope axes.

The use of prior distribution information may be extended to morecomplex cases. For example, in some embodiments, the desired calibrationcurve is not linear (e.g., it has three or more parameters). In suchcases, the most probable set of parameters (e.g., based on the priordistributions) the still correlates with the calibration data may beused to define the calibration curve.

In these various embodiments, utilizing an additional electrode, priorinformation (e.g., in vitro or in vivo testing), signal processing, orother information for assisting in the calibration process can be usedalone or in combination to reduce or eliminate the dependency of thecalibration on reference analyte values obtained by the host.

Referring again to FIG. 21, at block 268, a sensor data transformationmodule uses the conversion function to transform sensor data intosubstantially real-time analyte value estimates, also referred to ascalibrated data, as sensor data is continuously (or intermittently)received from the sensor. For example, in the embodiment of FIG. 22A,the sensor data, which can be provided to the receiver in “counts,” istranslated to estimate analyte value(s) in mg/dL. In other words, theoffset value at any given point in time can be subtracted from the rawvalue (e.g., in counts) and divided by the slope to obtain the estimatedanalyte value:

${{mg}\text{/}{dL}} = \frac{\left( {{rawvalue} - {offset}} \right)}{slope}$

In some alternative embodiments, the sensor and/or reference analytevalues are stored in a database for retrospective analysis.

At block 269, an output module provides output to the user via the userinterface. The output is representative of the estimated analyte value,which is determined by converting the sensor data into a meaningfulanalyte value such as described in more detail with reference to block268, above. User output can be in the form of a numeric estimatedanalyte value, an indication of directional trend of analyteconcentration, and/or a graphical representation of the estimatedanalyte data over a period of time, for example. Other representationsof the estimated analyte values are also possible, for example audio andtactile. Accordingly, after initial calibration of the sensor, andpossibly determination of stability of the sensor data, real-timecontinuous analyte information can be displayed on the user interface sothat the user can regularly and proactively care for his/her diabeticcondition within the bounds set by his/her physician.

In alternative embodiments, the conversion function is used to predictanalyte values at future points in time. These predicted values can beused to alert the user of upcoming hypoglycemic or hyperglycemic events.Additionally, predicted values can be used to compensate for the timelag (e.g., 15 minute time lag such as described elsewhere herein), sothat an estimate analyte value displayed to the user represents theinstant time, rather than a time delayed estimated value.

In some embodiments, the substantially real time estimated analytevalue, a predicted future estimate analyte value, a rate of change,and/or a directional trend of the analyte concentration is used tocontrol the administration of a constituent to the user, including anappropriate amount and time, in order to control an aspect of the user'sbiological system. One such example is a closed loop glucose sensor andinsulin pump, wherein the analyte data (e.g., estimated glucose value,rate of change, and/or directional trend) from the glucose sensor isused to determine the amount of insulin, and time of administration,that can be given to a diabetic user to evade hyper- and hypoglycemicconditions.

The conventional analyte meters (e.g., self-monitored blood analytetests) are known to have a +−20% error in analyte values. For example,gross errors in analyte readings are known to occur due to patient errorin self-administration of the blood analyte test. In one such example,if the user has traces of sugar on his/her finger while obtaining ablood sample for a glucose concentration test, then the measured glucosevalue will likely be much higher than the actual glucose value in theblood. Additionally, it is known that self-monitored analyte tests(e.g., test strips) are occasionally subject to manufacturing error.

Another cause for error includes infrequency and time delay that canoccur if a user does not self-test regularly, or if a user self-testsregularly but does not enter the reference value at the appropriate timeor with the appropriate time stamp. Providing reference data using asubstantially continuous sensor overcomes those errors associated withirregular self-tests. To ensure the validity of the sensor data, thereceiver can be configured to evaluate the clinical acceptability ofreceived reference analyte data prior to their acceptance as a validreference value.

In one embodiment, the reference analyte data (and/or sensor analytedata) is evaluated with respect to substantially time correspondingsensor data (and/or substantially time corresponding reference analytedata) to determine the clinical acceptability of the reference analyteand/or sensor analyte data. Clinical acceptability considers a deviationbetween time corresponding glucose measurements (e.g., data from aglucose sensor and data from a reference glucose monitor) and the risk(e.g., to the decision making of a diabetic patient) associated withthat deviation based on the glucose value indicated by the sensor and/orreference data. Evaluating the clinical acceptability of reference andsensor analyte data, and controlling the user interface dependentthereon, can minimize clinical risk.

In one embodiment, the receiver evaluates clinical acceptability eachtime reference data is obtained. In another embodiment, the receiverevaluates clinical acceptability after the initial calibration andstabilization of the sensor, such as described with reference to FIG.21, above. In some embodiments, the receiver evaluates clinicalacceptability as an initial pre-screen of reference analyte data, forexample after determining if the reference glucose measurement is fromabout 40 to about 400 mg/dL. In other embodiments, other methods ofpre-screening data can be used, for example by determining if areference analyte data value is physiologically feasible based onprevious reference analyte data values (e.g., below a maximum rate ofchange).

After initial calibration such as described in more detail withreference to FIG. 21, the sensor data receiving module 261 receivessubstantially continuous sensor data (e.g., a data stream) via areceiver and converts that data into estimated analyte values. As usedherein, “substantially continuous” is broad enough to include a datastream of individual measurements taken at time intervals (e.g.,time-spaced) of from fractions of a second up to, e.g., 1, 2, or 5minutes. As sensor data is continuously converted, it can beoccasionally recalibrated such as described in more detail below withreference to FIG. 24. Initial calibration and re-calibration of thesensor requires a reference analyte value. Accordingly, the receiver canreceive reference analyte data at any time for appropriate processing.These reference analyte values can be evaluated for clinicalacceptability such as described below as a fail-safe against referenceanalyte test errors.

In some embodiments, the reference data is pre-screened according toenvironmental and physiological issues, such as time of day, oxygenconcentration, postural effects, and patient-entered environmental data.In one example embodiment, wherein the sensor comprises an implantableglucose sensor, an oxygen sensor within the glucose sensor is used todetermine if sufficient oxygen is being provided to successfullycomplete the necessary enzyme and electrochemical reactions for glucosesensing. In another example embodiment wherein the sensor comprises animplantable glucose sensor, the counter electrode could be monitored fora “rail-effect”, that is, when insufficient oxygen is provided at thecounter electrode causing the counter electrode to reach operational(e.g., circuitry) limits.

In some embodiments, a clinical acceptability evaluation module in thereceiver (not shown), also referred to as a clinical module, evaluatesnewly received reference data and/or time corresponding sensor data. Insome embodiments of evaluating clinical acceptability, the rate ofchange of the reference data as compared to previous data is assessedfor clinical acceptability. That is, the rate of change and acceleration(or deceleration) of many analytes has certain physiological limitswithin the body. Accordingly, a limit can be set to determine if the newmatched pair is within a physiologically feasible range, indicated by arate of change from the previous data that is within known physiologicaland/or statistical limits. Similarly, in some embodiments any algorithmthat predicts a future value of an analyte can be used to predict andthen compare an actual value to a time corresponding predicted value todetermine if the actual value falls within a clinically acceptable rangebased on the predictive algorithm, for example.

In one exemplary embodiment, the clinical acceptability evaluationmodule matches the reference data with a substantially timecorresponding converted sensor value such as described with reference toFIG. 21 above, and plots the matched data on a Clarke Error Grid such asdescribed in more detail with reference to FIG. 23.

FIG. 23 is a graph of two data pairs on a Clarke Error Grid toillustrate the evaluation of clinical acceptability in one exemplaryembodiment. The Clarke Error Grid can be used by the clinicalacceptability evaluation module to evaluate the clinical acceptabilityof the disparity between a reference glucose value and a sensor glucose(e.g., estimated glucose) value, if any, in an embodiment wherein thesensor is a glucose sensor. The x-axis represents glucose referenceglucose data and the y-axis represents estimated glucose sensor data.Matched data pairs are plotted accordingly to their reference and sensorvalues, respectively. In this embodiment, matched pairs that fall withinthe A and B regions of the Clarke Error Grid are considered clinicallyacceptable, while matched pairs that fall within the C, D, and E regionsof the Clarke Error Grid are not considered clinically acceptable.Particularly, FIG. 23 shows a first matched pair 1992 is shown whichfalls within the A region of the Clarke Error Grid, therefore is itconsidered clinically acceptable. A second matched pair 94 is shownwhich falls within the C region of the Clarke Error Grid, therefore itis not considered clinically acceptable. Further description ofevaluating reference data for its clinical acceptability is included inU.S. Publication No. US-2005-0027180-A1.

Reference is now made to FIG. 24, which is a flow chart that illustratesthe process of evaluation of calibration data for best calibration basedon inclusion criteria of matched data pairs in one embodiment.

Calibration of analyte sensors can be variable over time; that is, theconversion function suitable for one point in time may not be suitablefor another point in time (e.g., hours, days, weeks, or months later).For example, in an embodiment wherein the analyte sensor issubcutaneously implantable, the maturation of tissue ingrowth over timecan cause variability in the calibration of the analyte sensor. Asanother example, physiological changes in the user (e.g., metabolism,interfering blood constituents, lifestyle changes) can cause variabilityin the calibration of the sensor. Accordingly, a continuously updatingcalibration algorithm is disclosed that includes reforming thecalibration set, and thus recalculating the conversion function, overtime according to a set of inclusion criteria.

At block 101, the reference data receiving module, also referred to asthe reference input module, receives one or more new reference analytevalues (e.g., data point) from the reference analyte source. In someembodiments, the reference analyte value can be pre-screened accordingto criteria such as described in more detail with reference to FIG. 21,block 62. In some embodiments, the reference analyte values can beevaluated for clinical acceptability such as described in more detailwith reference to FIG. 23.

At block 102, the data matching module, also referred to as theprocessor module, forms one or more updated matched data pairs bymatching new reference data to substantially time corresponding sensordata, such as described in more detail with reference to FIG. 21, block63.

At block 103, a calibration evaluation module evaluates the new matchedpair(s) inclusion into the calibration set. In some embodiments, thereceiver simply adds the updated matched data pair into the calibrationset, displaces the oldest and/or least concordant matched pair from thecalibration set, and proceeds to recalculate the conversion functionaccordingly (block 105).

In some embodiments, the calibration evaluation includes evaluating onlythe new matched data pair. In some embodiments, the calibrationevaluation includes evaluating all of the matched data pairs in theexisting calibration set and including the new matched data pair; insuch embodiments not only is the new matched data pair evaluated forinclusion (or exclusion), but additionally each of the data pairs in thecalibration set are individually evaluated for inclusion (or exclusion).In some alternative embodiments, the calibration evaluation includesevaluating all possible combinations of matched data pairs from theexisting calibration set and including the new matched data pair todetermine which combination best meets the inclusion criteria. In someadditional alternative embodiments, the calibration evaluation includesa combination of at least two of the above-described embodiments.

Inclusion criteria comprise one or more criteria that define a set ofmatched data pairs that form a substantially optimal calibration set.One inclusion criterion comprises ensuring the time stamp of the matcheddata pairs (that make up the calibration set) span at least a set timeperiod (e.g., three hours). Another inclusion criterion comprisesensuring that the time stamps of the matched data pairs are not morethan a set age (e.g., one week old). Another inclusion criterion ensuresthat the matched pairs of the calibration set have a substantiallydistributed amount of high and low raw sensor data, estimated sensoranalyte values, and/or reference analyte values. Another criterioncomprises ensuring all raw sensor data, estimated sensor analyte values,and/or reference analyte values are within a predetermined range (e.g.,40 to 400 mg/dL for glucose values). Another criterion comprisesevaluating the rate of change of the analyte concentration (e.g., fromsensor data) during the time stamp of the matched pair(s). For example,sensor and reference data obtained during the time when the analyteconcentration is undergoing a slow rate of change can be lesssusceptible inaccuracies caused by time lag and other physiological andnon-physiological effects. Another criterion comprises evaluating thecongruence of respective sensor and reference data in each matched datapair; the matched pairs with the most congruence can be chosen. Anothercriterion comprises evaluating physiological changes (e.g., low oxygendue to a user's posture that can effect the function of a subcutaneouslyimplantable analyte sensor, or other effects such as described withreference to FIG. 21) to ascertain a likelihood of error in the sensorvalue. Valuation of calibration set criteria can comprise evaluatingone, some, or all of the above described inclusion criteria. It iscontemplated that additional embodiments can comprise additionalinclusion criteria not explicitly described herein.

At block 104, the evaluation of the calibration set determines whetherto maintain the previously established calibration set, or if thecalibration set can be updated (e.g., modified) with the new matcheddata pair. In some embodiments, the oldest matched data pair is simplydisplaced when a new matched data pair is included. A new calibrationset can include not only the determination to include the new matcheddata pair, but in some embodiments, can also determine which of thepreviously matched data pairs can be displaced from the calibration set.

At block 105, the conversion function module recreates the conversionfunction using the modified calibration set. The calculation of theconversion function is described in more detail with reference to FIG.21.

At block 106, the sensor data transformation module converts sensor datato calibrated data using the updated conversion function. Conversion ofraw sensor data into estimated analyte values is described in moredetail with reference to FIG. 21.

Reference is now made to FIG. 25, which is a flow chart that illustratesthe process of evaluating the quality of the calibration in oneembodiment. The calibration quality can be evaluated by determining thestatistical association of data that forms the calibration set, whichdetermines the confidence associated with the conversion function usedin calibration and conversion of raw sensor data into estimated analytevalues.

In one embodiment calibration quality can be evaluated after initial orupdated calculation of the conversion function such as describedelsewhere herein. However, calibration quality can be performed at anytime during the data processing.

At block 111, a sensor data receiving module, also referred to as thesensor data module, receives the sensor data from the sensor such asdescribed in more detail with reference to FIG. 21.

At block 112, a reference data receiving module, also referred to as thereference input module, receives reference data from a reference analytesource, such as a substantially continuous analyte monitor, and asdescribed in more detail with reference to FIG. 21.

At block 113, the data matching module, also referred to as theprocessor module, matches received reference data with substantiallytime corresponding sensor data to provide one or more matched datapairs, such as described in more detail with reference to FIG. 21.

At block 114, the calibration set module, also referred to as theprocessor module, forms a calibration set from one or more matched datapairs such as described in more detail with reference to FIGS. 21 and24.

At block 115, the conversion function module calculates a conversionfunction using the calibration set, such as described in more detailwith reference to FIGS. 21 and 16.

At block 116, the sensor data transformation module continuously (orintermittently) converts received sensor data into estimated analytevalues, also referred to as calibrated data, such as described in moredetail with reference to FIGS. 21 and 24.

At block 117, a quality evaluation module evaluates the quality of thecalibration. In one embodiment, the quality of the calibration is basedon the association of the calibration set data using statisticalanalysis. Statistical analysis can comprise any known cost function suchas linear regression, non-linear mapping/regression, rank (e.g.,non-parametric) correlation, least mean square fit, mean absolutedeviation (MAD), mean absolute relative difference, and the like. Theresult of the statistical analysis provides a measure of the associationof data used in calibrating the system. A threshold of data associationcan be set to determine if sufficient quality is exhibited in acalibration set.

In another embodiment, the quality of the calibration is determined byevaluating the calibration set for clinical acceptability, such asdescribed with reference to blocks 82 and 83 (e.g., Clarke Error Grid,Consensus Grid, or clinical acceptability test). As an example, thematched data pairs that form the calibration set can be plotted on aClarke Error Grid, such that when all matched data pairs fall within theA and B regions of the Clarke Error Grid, then the calibration isdetermined to be clinically acceptable.

In yet another alternative embodiment, the quality of the calibration isdetermined based initially on the association of the calibration setdata using statistical analysis, and then by evaluating the calibrationset for clinical acceptability. If the calibration set fails thestatistical and/or the clinical test, the processing returns to block115 to recalculate the conversion function with a new (e.g., optimized)set of matched data pairs. In this embodiment, the processing loop(block 115 to block 117) iterates until the quality evaluation module 1)determines clinical acceptability, 2) determines sufficient statisticaldata association, 3) determines both clinical acceptability andsufficient statistical data association, or 4) surpasses a threshold ofiterations; after which the processing continues to block 118.

FIGS. 26A and 26B illustrate one exemplary embodiment wherein theaccuracy of the conversion function is determined by evaluating thecorrelation coefficient from linear regression of the calibration setthat formed the conversion function. In this exemplary embodiment, athreshold (e.g., 0.79) is set for the R-value obtained from thecorrelation coefficient.

FIG. 26A and 26B are graphs that illustrate an evaluation of the qualityof calibration based on data association in one exemplary embodimentusing a correlation coefficient. Particularly, FIGS. 26A and 26Bpictorially illustrate the results of the linear least squaresregression performed on a first and a second calibration set (FIGS. 26Aand 26B, respectively). The x-axis represents reference analyte data;the y-axis represents sensor data. The graph pictorially illustratesregression that determines the conversion function.

The regression line (and thus the conversion function) formed by theregression of the first calibration set of FIG. 26A is the same as theregression line (and thus the conversion function) formed by theregression of the second calibration set of FIG. 26B. However, thecorrelation of the data in the calibration set to the regression line inFIG. 26A is significantly different than the correlation of the data inthe calibration set to the regression line in FIG. 26A. In other words,there is a noticeably greater deviation of the data from the regressionline in FIG. 26B than the deviation of the data from the regression linein FIG. 26A.

In order to quantify this difference in correlation, an R-value can beused to summarize the residuals (e.g., root mean square deviations) ofthe data when fitted to a straight line via least squares method, inthis exemplary embodiment. R-value can be calculated according to thefollowing equation:

$R = \frac{\sum\limits_{i}{\left( {x_{i} - \overset{\_}{x}} \right)\left( {y_{i} - \overset{\_}{y}} \right)}}{\sqrt{\sum\limits_{i}\left( {x_{i} - x} \right)^{2}}\sqrt{\left. {{\sum\limits_{i}y_{i}} - y} \right)^{2}}}$

In the above equation: i is an index (1 to n), x is a reference analytevalue, y is a sensor analyte value, x is an average of 1/n referenceanalyte values, and y is an average of 1/n sensor analyte values.

In the exemplary calibration set shown in FIG. 26A, the calculatedR-value is about 0.99, which can also be expressed as the correlationcoefficient of regression. Accordingly, the calibration exhibitssufficient data association (and thus insufficient quality) because itfalls above the 0.79 threshold set in this exemplary embodiment.

In the exemplary calibration set shown in FIG. 26B, the calculatedR-value is about 0.77, which can also be expressed as the correlationcoefficient of regression. Accordingly, the calibration exhibitsinsufficient data association (and thus insufficient quality) because itfalls below the 0.79 threshold set in this exemplary embodiment.

Reference is again made to FIG. 25, at block 118, the interface controlmodule, also referred to as the fail-safe module, controls the userinterface based upon the quality of the calibration. If the calibrationis exhibits sufficient quality, then the then the first referenceanalyte value is discarded, and the repeated reference analyte value isaccepted the process continues, and the user interface can function asnormal; that is providing output for the user such as described in moredetail with reference to FIG. 21. If however the calibration is notdeemed sufficient in quality, then fail-safe module begins the initialstages of fail-safe mode, which are described in more detail in U.S.Publication No. US-2005-0027463-A1.

Example I

As described above, benchtop testing of a sensor prior to insertion canbe used to calibrate sensor data after the sensor is inserted. FIG. 27shows in-vivo sensitivity (as calculated using retrospectivecalibration) vs. in-vitro sensitivity (collected prior to implant), of16 short term sensors implanted in humans. Least-squares regression wasused to define the predictive relationship between in-vitro and in-vivosensitivities (e.g., m_(in vivo)=2.99*M_(in vitro)+26.62), as shown inFIG. 27. This relationship was applied to a sensor used in theabove-described experiment. The comparison of blood glucose values withthe in-vitro calibrated sensor is shown in FIGS. 28 and 29. Predictedin-vivo sensitivity was assumed for calibration throughout the firstday. The mean absolute relative difference found across 43 matched pairsover 3 days was 20.17%. In-vivo sensitivity is usually greater thanin-vitro sensitivity (typically 2-3× higher). This may be due toenhanced transport of glucose when the membranes interact with moleculesin the tissues, such as proteins or lipid in the interstitial fluid.

Example II

In this example, one substantially continuous glucose sensor was used tocalibrate another substantially continuous glucose sensor, where bothsensors were used in the same host. The data specifically illustratesthe use of a short-term (e.g., transcutaneous) sensor to calibrate along term (e.g., implantable) sensor, but the methods described areapplicable to other combinations, including (1) use of a short-termsensor to calibrate another short term sensor; (2) use of a long-termsensor to calibrate another long-term sensor; (3) use of a long termsensor to calibrate a short term sensor.

As discussed herein, calibration of an enzyme-electrode based glucosesensor consists of solving the line

y=mx+b

for m and b, where y denotes the sensor signal (in units of A/D counts),x the estimated glucose concentration (mg/dl), m the sensor sensitivityto glucose (counts/mg/dl), and b the baseline signal unrelated toglucose (counts). If two glucose sensors are used concurrently in thesame host, and one sensor is calibrated, the time-corresponding glucosevalues (x) from the calibrated sensor can be matched to the signalvalues (y) of the un-calibrated sensor. These matched pairs are thenused to draw the calibration line for the second sensor using aregression relationship (e.g. ordinary least-squares).

In this example, a short term substantially continuous sensor wasemployed in a host in which a long term sensor was already implanted.The data from the substantially continuous short term sensor was used torun a prospective calibration on the substantially continuous long termsensor. Referring to FIG. 30, a plurality of data points (e.g., about20) from the short term sensor (referred to in FIG. 30 as “STS” anddepicted with a diamond symbol) were used as reference data to calibratethe sensor data from the long term sensor (referred to in FIG. 30 as“LTS” and depicted with a dot symbol). The top graph in FIG. 30 showssensor data (counts (left y-axis)) from an un-calibrated long termsensor and sensor data (glucose measurements (right y-axis)) from acalibrated short term sensor. The top graph in FIG. 30 shows roughly 6days of un-calibrated long term sensor data for a particular host. Onday five, a calibrated short term sensor was employed on the same host.The lower graph in FIG. 30 shows a close-up of the overlay of the sensordata from the long term sensor and, beginning on day five, the sensordata from the short term sensor.

After matching time-corresponding sensor values from the short termsensor data and the long term sensor data, a regression analysis yieldeda result for (m, b) of (134.24, 11922.53), with 5 min time-lag of thelong term sensor relative to short term sensor. When this calibrationwas prospectively applied to the long term sensor on day 6, the(calibrated) long term sensor glucose values were compared to referenceglucose measurements (e.g. meter readings) to demonstrate calibrationaccuracy, as shown in FIG. 23. In FIG. 31, the long term sensor data isreferred to as “LTS” and depicted as small dots, and the referenceglucose measurements (self-monitoring blood glucose) are referred to as“SMBG” and depicted with large ovals. The results show the accuracy ofthe short term sensor calibration. Further improvement in accuracy wouldlikely result if more points were used.

Comparison of the proposed calibration scheme (long term sensorcalibration based on short term sensor) vs. a conventional scheme, forexample, a 6-pt moving window regression, using 2/day self-monitoringblood glucose (SMBG) is shown in the Table 1.

TABLE 1 Calibration long term sensor calibration schemes: retrospective,with SMBG, and with short term sensor. With SMBG Calibration SchemeRetrospective (conventional) With STS m 127.12 197.38 134.24 b 12196.4813508.15 11922.53

The results suggest that calibration of a long term sensor with a shortterm sensor can be more accurate than with 2/day SMBG. The m and b foundwith short term sensor based calibration are closer to the values foundwith retrospective calibration (‘gold standard’) than with 2/day SMBG.

Example III

Referring now to FIG. 32, in this example, sensor data from a short termanalyte sensor was used to calibrate a subsequently employed short termsensor. Short term data was collected over a two and a half-day timeperiod from a substantially continuous short term sensor employed on ahuman host. Finger stick glucose measurements (referred to in FIG. 32 as“Calpts” and depicted with large round dots) were used to calibrateSensor No. 1. Glucose values (read off of the left y-axis) were derivedfrom the Calibrated Sensor No. 1 sensor data. The Calibrated Sensor No.1 data is referred to in FIG. 32 as “Calglucose 1” and depicted as smalldots.

On Day 3, a second substantially continuous short term sensor (referredto in FIG. 32 as “Sensor2”) was employed on the same host as Sensor No.1, and sensor data was collected about every 5 minutes for one day(e.g., 288 data points). Digital count data (read off of the righty-axis) from the Sensor No. 2 is depicted in FIG. 32 as diamonds.

Using the glucose values resulting from the data of Sensor No. 1, thesensor data from Sensor No. 2 was calibrated using a retrospectivecalibration analysis, i.e., least squares regression correlationcoefficient, and evaluated using a mean absolute relative difference(MARD). The results of the regression are illustrated in FIG. 33, whichshows 288 digital count data points from Sensor No. 2 matched to glucosevalues from Sensor No. 1 at corresponding times. The regression data wasthen prospectively applied to the data collected by Sensor No. 2 on Day4. The Calibrated Sensor 2 data is depicted in FIG. 32 as medium-sizedround dots and referred to in FIG. 32 as “Calglucose2.” After one day, afinger stick glucose measurement was taken at about 12:00:00. The sensordata from FIG. 32 closely corresponded to the glucose measurement fromthe finger stick glucose measurement.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. Pat. No.4,994,167; U.S. Pat. No. 4,757,022; U.S. Pat. No. 6,001,067; U.S. Pat.No. 6,741,877; U.S. Pat. No. 6,702,857; U.S. Pat. No. 6,558,321; U.S.Pat. No. 6,931,327; and U.S. Pat. No. 6,862,465.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. PublicationNo. US-2005-0176136-A1; U.S. Publication No. US-2005-0251083-A1; U.S.Publication No. US-2005-0143635-A1; U.S. Publication No.US-2005-0181012-A1; U.S. Publication No. US-2005-0177036-A1; U.S.Publication No. US-2005-0124873-A1; U.S. Publication No.US-2005-0051440-A1; U.S. Publication No. US-2005-0115832-A1; U.S.Publication No. US-2005-0245799-A1; U.S. Publication No.US-2005-0245795-A1; U.S. Publication No. US-2005-0242479-A1; U.S.Publication No. US-2005-0182451-A1; U.S. Publication No.US-2005-0056552-A1; U.S. Publication No. US-2005-0192557-A1; U.S.Publication No. US-2005-0154271-A1; U.S. Publication No.US-2004-0199059-A1; U.S. Publication No. US-2005-0054909-A1; U.S.Publication No. US-2005-0112169-A1; U.S. Publication No.US-2005-0051427-A1; U.S. Publication No. US-2003-0032874-A1; U.S.Publication No. US-2005-0103625-A1; U.S. Publication No.US-2005-0203360-A1; U.S. Publication No. US-2005-0090607-A1; U.S.Publication No. US-2005-0187720-A1; U.S. Publication No.US-2005-0161346-A1; U.S. Publication No. US-2006-0015020-A1; U.S.Publication No. US-2005-0043598-A1; U.S. Publication No.US-2003-0217966-A1; U.S. Publication No. US-2005-0033132-A1; U.S.Publication No. US-2005-0031689-A1; U.S. Publication No.US-2004-0045879-A1; U.S. Publication No. US-2004-0186362-A1; U.S.Publication No. US-2005-0027463-A1; U.S. Publication No.US-2005-0027181-A1; U.S. Publication No. US-2005-0027180-A1; U.S.Publication No. US-2006-0020187-A1; U.S. Publication No.US-2006-0036142-A1; U.S. Publication No. US-2006-0020192-A1; U.S.Publication No. US-2006-0036143-A1; U.S. Publication No.US-2006-0036140-A1; U.S. Publication No. US-2006-0019327-A1; U.S.Publication No. US-2006-0020186-A1; U.S. Publication No.US-2006-0020189-A1; U.S. Publication No. US-2006-0036139-A1; U.S.Publication No. US-2006-0020191-A1; U.S. Publication No.US-2006-0020188-A1; U.S. Publication No. US-2006-0036141-A1; U.S.Publication No. US-2006-0020190-A1; U.S. Publication No.US-2006-0036145-A1; U.S. Publication No. US-2006-0036144-A1; and U.S.Publication No. US-2006-0016700-A1.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. applicationSer. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHODFOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 11/280,672filed Nov. 16, 2005, and entitled “TECHNIQUES TO IMPROVE POLYURETHANEMEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S. application Ser. No.11/280,102 filed Nov. 16, 2005, and entitled “TECHNIQUES TO IMPROVEPOLYURETHANE MEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S.application Ser. No. 11/201,445 filed Aug. 10, 2005 and entitled “SYSTEMAND METHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S. application Ser.No. 11/335,879 filed Jan. 18, 2006 and entitled “CELLULOSIC-BASEDINTERFERENCE DOMAIN FOR AN ANALYTE SENSOR”; U.S. application Ser. No.11/334,876 filed Jan. 18, 2006 and entitled “TRANSCUTANEOUS ANALYTESENSOR”; U.S. application Ser. No. 11/333,837 filed Jan. 17, 2006 andentitled “LOW OXYGEN IN VIVO ANALYTE SENSOR”.

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

1. A method for analyzing data from an analyte sensor, the methodcomprising: receiving data from the analyte sensor, the data comprisingat least one sensor data point; receiving reference data from areference analyte monitor, the reference data comprising at least onereference data point; and determining an acceptability of the sensordata or the reference data by subjecting the reference data andsubstantially time-corresponding sensor data to a boundary testutilizing boundaries.
 2. The method of claim 1, wherein the boundariesare derived from prior information.
 3. The method of claim 2, whereinthe prior information comprises information obtained from at least oneof in vivo testing of at least one analyte sensor and in vivo use of atleast one analyte sensor.
 4. The method of claim 1, further comprising astep of determining acceptability of the reference data, wherein apositive determination of acceptability is determined when the referencedata and substantially time-corresponding sensor data fall within theboundaries of the boundary test.
 5. The method of claim 4, furthercomprising using the reference data for calibration of the analytesensor in response to a positive determination of acceptability.
 6. Themethod of claim 4, further comprising requesting additional referencedata in response to a negative determination of acceptability.
 7. Themethod of claim 6, further comprising determining acceptability of theadditional reference data, wherein a positive determination ofacceptability is determined when the additional reference data andsubstantially time-corresponding sensor data fall within the boundariesof the boundary test.
 8. The method of claim 7, further comprising usingthe additional reference data for calibration of the analyte sensor inresponse to a positive determination of acceptability of the additionalreference data.
 9. The method of claim 7, further comprising using thereference data for calibration of the analyte sensor if the additionalreference data substantially corresponds to the reference data.
 10. Asystem for analyzing data from an analyte sensor, the system comprising:a sensor data receiving module configured to receive sensor data fromthe analyte sensor, the sensor data comprising at least one sensor datapoint; a reference data receiving module configured to receive referencedata from a reference analyte monitor, the reference data comprising atleast one reference data point; and a processor module configured todetermine an acceptability of the sensor data or the reference data bysubjecting the reference data and substantially time-correspondingsensor data to a boundary test utilizing boundaries.
 11. The system ofclaim 10, wherein the boundaries are derived from prior information. 12.The system of claim 11, wherein the prior information comprisesinformation obtained from at least one of in vivo testing of at leastone analyte sensor and in vivo use of at least one analyte sensor. 13.The system of claim 10, wherein the processor module is configured todetermine an acceptability of the reference data, wherein a positivedetermination of acceptability is determined when the reference data andsubstantially time-corresponding sensor data fall within the boundariesof the boundary test.
 14. The system of claim 13, wherein the processormodule is configured to use the reference data for calibration of theanalyte sensor in response to a positive determination of acceptability.15. The system of claim 13, wherein the processor module is configuredto request additional reference data in response to a negativedetermination of acceptability.
 16. The system of claim 15, wherein theprocessor module is configured to determine acceptability of theadditional reference data, wherein a positive determination ofacceptability is determined when the additional reference data andsubstantially time corresponding sensor data fall within the boundariesof the boundary test.
 17. The system of claim 16, wherein the processormodule is configured to use the additional reference data forcalibration of the analyte sensor in response to a positivedetermination of acceptability of the additional reference data.
 18. Thesystem of claim 16, wherein the processor module is configured to usethe reference data for calibration of the analyte sensor if theadditional reference data substantially corresponds to the referencedata.
 19. A system for analyzing data from an analyte sensor, the systemcomprising: a sensor data receiving module configured to receive sensordata from the analyte sensor, the sensor data comprising at least onesensor data point; a reference data receiving module configured toreceive reference data from a reference analyte monitor, the referencedata comprising at least one reference data point; and a processormodule configured to perform outlier detection on the reference data orthe sensor data, wherein the processor module is further configured tocalibrate the analyte sensor.
 20. The system of claim 19, wherein theprocessor module is configured to calibrate the analyte sensor after thesystem has successfully passed outlier detection.
 21. The system ofclaim 19, wherein outlier detection comprises comparing reference dataand time-corresponding sensor data to a boundary test.
 22. The system ofclaim 19, wherein the processor module is configured to detect noise inthe sensor signal.
 23. The system of claim 22, wherein the processormodule is configured to calibrate the analyte sensor only when noise issubstantially not detected in the sensor signal.